KR20220041084A - Alcohol derivatives as KV7 potassium channel openers - Google Patents

Abstract

The present invention provides novel compounds that activate Kv7 potassium channels. A separate aspect of the invention relates to pharmaceutical compositions comprising said compounds and to the use of the compounds for the treatment of disorders responsive to activation of Kv7 potassium channels.

Description

Alcohol derivatives as KV7 potassium channel openers

The present invention relates to novel compounds that activate Kv7 potassium channels. A separate aspect of the invention relates to pharmaceutical compositions comprising said compounds and to the use of the compounds for the treatment of disorders responsive to activation of Kv7 potassium channels.

Voltage-dependent potassium (Kv) channels can modulate cell excitability by conducting potassium ions (K ⁺ ) across the cell membrane in response to changes in membrane potential, thereby modulating (increasing or decreasing) the cell's electrical activity. Functional Kv channels exist as polyhedral structures formed by the association of four alpha subunits and four beta subunits. The alpha subunit contains six transmembrane domains, a pore-forming loop and a voltage-sensor, and is symmetrically arranged around the central pore. A beta or auxiliary subunit can interact with the alpha subunit and modify the properties of the channel complex, including, but not limited to, altering the electrophysiological or biophysical properties, expression level or expression pattern of the channel. there is.

Nine Kv channel alpha subunit families have been identified and are termed Kv1-Kv9. Therefore, there is a great deal of diversity in Kv channel function that arises as a result of the multiplicity of subfamilies, the formation of both homozygous and heterozygous subunits within the subfamily, and the additional effects of association with beta subunits (Christie, 25 Clinical and Experimental Pharmacology and Physiology, 1995, 22, 944-951).

The Kv7 channel family comprises at least five members comprising one or more of the mammalian channels of Kv7.1, Kv7.2, Kv7.3, Kv7.4, Kv7.5 and any mammalian or non-mammalian equivalent or variant thereof rice variant). Alternatively, members of this family are designated by the gene names KCNQ1, KCNQ2, KCNQ3, KCNQ4 and KCNQ5, respectively (Dalby-Brown, et al., Current Topics in Medicinal Chemistry, 2006, 6, 9991023).

As mentioned above, neuronal Kv7 potassium channels play a role in controlling neuronal excitability. The Kv7 channel, in particular the Kv7.2/Kv7.3 heterodimer, underlies the M-current (Wang et al Science. 1998 Dec 4:282(5395):1890-3). The M-current has the characteristic time- and voltage-dependent properties of stabilizing the membrane potential in response to multiple excitatory stimuli.

In this way, M-currents are involved in controlling neuronal excitability (Delmas & Brown, Nature, 2005, 6, 850-862). The M-current is a non-inactivating potassium current found in many neuronal cell types. In each cell type, it dominates in controlling membrane excitability in that it is the only sustained current in the range of action potential initiation (Marrion, Annual Review Physiology 1997, 59, 483-504).

Retigabine (N-(2-amino-4-(4-fluorobenzylamino)-phenyl)carbamic acid ethyl ester) is a compound that binds to the Kv7 potassium channel (Wuttke, et al., Molecular Pharmacology, 2005, 67). , 1009-1017). Retigabine activates K ⁺ currents in neuronal cells, and the pharmacology of this induced current is in agreement with the published pharmacology of M-channels correlated with Kv7.2/3 K ⁺ channel heteromultimers, indicating that Kv7.2 It is suggested that activation of the /3 channel is responsible for at least part of the anticonvulsant activity of this substance (Wickenden, et al., Molecular Pharmacology 2000, 58, 591-600). Retigabine is effective in reducing the incidence of seizures in epileptic patients (Bialer, et al., Epilepsy Research 2002, 51, 31-71). Retigabine has broad spectrum and potent anticonvulsant properties. It is active following oral and intraperitoneal administration in rats and mice in various anticonvulsant trials (Rostock, et al., Epilepsy Research 1996, 23, 211-223).

Five members of this family of ion channels differ in expression patterns. Expression of Kv7.1 is restricted to the heart, peripheral epithelium, and smooth muscle, whereas expression of Kv7.2, Kv7.3, Kv7.4 and Kv7.5 appears to be predominant in the nervous system, indicating that the hippocampus, cortex, ventral tegmental region and dorsal root ganglion neurons (for review, see Greene & Hoshi, Cellular and Molecular Life Sciences, 2017, 74(3), 495-508).

The KCNQ2 and KCNQ3 genes appear to be mutated in a genetic form of epilepsy known as benign familial neonatal seizures (Rogawski, Trends in Neurosciences 2000, 23, 393-398). Proteins encoded by the KCNQ2 and KCNQ3 genes are localized in cone neurons of the human cortex and hippocampus, regions of the brain involved in seizure generation and propagation (Cooper et al., Proceedings National Academy of Science USA 2000, 97, 4914-4919). ).

Moreover, mRNAs for Kv7.3 and 5 in addition to those for Kv7.2 are expressed in astrocytes and glial cells. As such, Kv7.2, Kv7.3 and Kv7.5 channels help modulate synaptic activity in the CNS and may contribute to the neuroprotective effect of KCNQ channel openers (Noda, et al., Society for Neuroscience Abstracts 2003, 53.9). ), which will be relevant to the treatment of neurodegenerative disorders such as, but not limited to, Alzheimer's disease, Parkinson's disease and Huntington's chorea.

mRNAs for the Kv7.2 and Kv7.3 subunits are found in brain regions associated with anxiety and emotional behaviors such as depression and bipolar disorder, such as the hippocampus, ventral tegmental region and amygdala (Saganich, et al. Journal of Neuroscience). 2001, 21, 4609-4624; Friedman et al., Nat Commun. 2016; 7: 11671.), retigabine is reported to be active in animal models of anxiety-like behavior (Korsgaard et al J Pharmacol Exp Ther. 2005 Jul.) ;314(1):282-92. Epub 2005 Apr 6.). The Kv7 channel is therefore implicated in the treatment of emotion-related disorders such as, but not limited to, bipolar depression, major depressive disorder, anxiety, suicide, panic attacks, social phobia.

The Kv7.2/3 channel has also been reported to be upregulated in models of neuropathic pain (Wickenden, et al., Society for Neuroscience Abstracts 2002, 454.7), and potassium channel modulators have been shown to be upregulated in both neuropathic pain and epilepsy. It was hypothesized to be active (Schroder, et al., Neuropharmacology 2001, 40, 888-898). Expression of mRNA for Kv7.2-5 in the trigeminal ganglion and dorsal root ganglion and trigeminal nerve coccyx suggests that, in addition to a role in neuropathic pain, openers of this channel may also influence the sensory process of migraine pain. (Goldstein, et al. Society for Neuroscience Abstracts 2003, 53.8). Taken together, this evidence suggests the relevance of KCNQ channel openers for the treatment of chronic pain and neuropathy-related disorders.

WO 07/90409 discloses the use of a Kv7 channel opener for the treatment of schizophrenia. Kv7 channel openers modulate the function of the dopaminergic system (Friedman et al., Nat Commun. 2016; Scotty et al J Pharmacol Exp Ther. 2009 Mar;328(3):951-62. doi: 10.1124/jpet.108.146944 Epub 2008 Dec 19; Koyama et al., J Neurophysiol. 2006 Aug;96(2):535-43. Epub 2006 Jan 4; Li et al Br J Pharmacol. 2017 Dec;174(23):4277-4294. doi: 10.1111/bph.14026. Epub 2017 Oct 19.; Hansen et al J Pharmacol Exp Ther. 2006 Sep;318(3):1006-19. Epub 2006 Jun 14), which is a psychiatric disorder, including but not limited to may be associated with the treatment of psychosis, mania, stress-related disorder, acute stress response, attention deficit/hyperactivity disorder, post-traumatic stress disorder, obsessive compulsive disorder, impulsive disorder, personality disorder, schizotypal disorder, aggression, and autism spectrum disorder. . WO 01/96540 discloses the use of modulators of the M-current formed by the expression of KCNQ2 and KCNQ3 genes for insomnia, whereas WO 01/092526 discloses that modulators of Kv7.5 can be used in the treatment of sleep disorder disorders. start that there is WO 09/015667 discloses the use of a Kv7 opener in the treatment of sexual dysfunction.

Although patients suffering from the aforementioned disorders may have available treatment options, many of these options lack the desired efficacy and are accompanied by undesirable side effects. Accordingly, there is an unmet need for novel therapeutic agents for the treatment of these disorders.

In an attempt to discover new therapeutic agents, the present inventors have identified a series of novel compounds as represented by formula (I). Accordingly, the present invention provides novel compounds as medicaments for the treatment of disorders modulated by KCNQ potassium channels.

The present invention relates to compounds of formula (I):

[Formula I]

In the above formula,

R 1 is selected from the group consisting of C ₁ -C ₆ alkyl, CF ₃ , CH ₂ CF ₃ , CF ₂ CHF ₂ , C ₃ -C ₈ cycloalkyl, said C ₃ -C ₈ cycloalkyl is one or two may be substituted with C ₁ -C ₃ alkyl, F, CHF ₂ or CF ₃ ,

R2 is H, C ₁ -C ₆ alkyl or CF ₃ ;

R1 and R2 taken together (with the carbon atom to which they are attached) form C ₃ -C ₅ cycloalkyl optionally substituted with one or two F, CHF ₂ or CF ₃ ;

R3 is C ₁ -C ₃ alkyl or CH ₂ OC _1-3 alkyl, said C ₁ -C ₃ alkyl or CH ₂ OC _1-3 alkyl is C≡N, 3 F or C ₃ -C ₅ cycloalkyl substituted;

R4 is selected from the group consisting of OCF ₃ or OCHF ₂ .

According to another aspect of the present invention, the present invention relates to a novel compound at the time of the present invention.

The present invention also relates to a pharmaceutical composition comprising a compound according to the present invention and a pharmaceutically acceptable carrier or excipient.

Moreover, the present invention relates to a method for treating a patient as described in the claims and embodiments, comprising administering to the subject a therapeutically effective amount of a compound according to the invention suffering from epilepsy, bipolar disorder, migraine and schizophrenia. including treatment of the patient.

According to one embodiment, the compound of formula (I) may have an R4 group which is OCF ₃ or OCHF ₂ .

According to another embodiment, the compound according to formula I may have an R3 group selected from the group comprising CH2-O-CF ₃ , CH2-O-cyclopropyl, CH2-C≡N.

According to a further embodiment, the compounds according to formula (I) may have a group R1 which is C ₃ -C ₄ cycloalkyl optionally substituted with 1 or 2 C ₁ -C ₃ alkyl, F, CHF ₂ or CF ₃ . .

In another embodiment, any compound according to formula (I) may have groups R1 and R2 which, taken together form cyclobutyl optionally substituted with one or two F, and R4 is OCF ₃ or OCHF ₂ .

According to a specific embodiment of the present invention, the compound according to the present invention is

(S)-N-((R)-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide;

(S)-N-((R)-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide;

(S)-N-((R)-1-(3-(trifluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide;

(S)-N-((S)-2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide;

(S)-N-((S)-3-cyano-1-(3-(trifluoromethoxy)phenyl)propyl)-3-hydroxy-4,4-dimethylpentanamide;

(R)-N-(2-cyclopropoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide ;

(R)-N-(2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide ;

(R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl) acetamide; or

(S)-N-(2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide

or a pharmaceutically acceptable salt of any of these compounds.

Another aspect of the present invention is

(R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide;

(S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide;

(S)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide;

(R)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide;

(R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoro -methyl)cyclopropyl)propanamide;

(S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoro -methyl)cyclopropyl)propanamide;

(R)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoro methyl)cyclopropyl)propanamide;

(S)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoro methyl)cyclopropyl)propanamide;

(R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)- 3-hydroxypropanamide;

(S)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)- 3-hydroxypropanamide;

(R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)- 3-hydroxypropanamide;

(S)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)- 3-hydroxypropanamide;

(S)-3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide;

(R)-3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide;

(S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxy propanamide;

(R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxy propanamide;

(S)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxy-4,4-dimethylpentanamide;

(S)-N-((S)-1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutyl)-3-hydroxy-4,4-dimethylpentanamide;

(S)-N-((S)-1-(3-(difluoromethoxy)phenyl)-3,3-difluoropropyl)-3-hydroxy-4,4-dimethylpentanamide;

(S)-N-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide;

(R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl) acetamide;

(R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl) acetamide;

(S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(difluoromethoxy)phenyl)butyl)acetamide;

(S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutyl)ah cetamide;

(S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(trifluoromethoxy)phenyl)propyl)acetamide;

(S)-N-(3,3-difluoro-1-(3-(trifluoromethoxy)phenyl)propyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)ah cetamide;

(S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide;

(R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydro oxybutanamide;

(S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydr oxybutanamide;

(S)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydr oxybutanamide;

(R)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydr oxybutanamide;

(R)-3-cyclopropyl-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide;

(S)-3-cyclopropyl-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide;

(R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy -3-methylpentanamide;

(S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy -3-methylpentanamide;

(R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide;

(S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide;

(S)—N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide;

(R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide;

(S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3- hydroxypropanamide;

(R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3- hydroxypropanamide;

( S )-3-cyclopentyl- N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide;

( R )-3-cyclopentyl- N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide;

( R )-3-(1-fluorocyclopropyl)-3-hydroxy- N -(( R )-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide;

and ( S )-3-(1-fluorocyclopropyl)-3-hydroxy- N -(( R )-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide

or a pharmaceutically acceptable salt of any of these compounds.

Reference to a compound encompassed by the present invention includes racemic mixtures of the compound to which it is related, as well as optically pure isomers as well as tautomeric forms of the compound to which it is related. Moreover, the compounds of the present invention can potentially exist in polymorphic and amorphous forms, or in unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol and others.

The invention also includes isotopically labeled forms of the compounds of the invention, such as deuterium. The compound could also be introduced into positron-emitting tomography (PET) studies to determine the distribution of positron emitting isotopes and receptors for medical imaging. Suitable positron emitting isotopes that may be incorporated into the compounds of the present invention are 11C, 13N, 15O and 18F. Isotopically labeled compounds of the present invention are generally prepared by conventional techniques known to those skilled in the art or by procedures analogous to those described in the accompanying examples using appropriate isotopically labeled reagents in place of unlabeled reagents. can be manufactured by

A compound according to the present invention may be in a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient or carrier.

In one embodiment, the invention relates to a compound according to the invention for use in therapy.

In another embodiment, the present invention relates to a method of treating a patient in need of such treatment comprising the step of administering to the subject a therapeutically effective amount of a compound according to the present invention, suffering from epilepsy, bipolar disorder, migraine or schizophrenia. .

In another embodiment, the present invention relates to psychosis, mania, stress related disorder, acute stress response, bipolar depression, major depressive disorder, anxiety, panic attack comprising administering to a subject a therapeutically effective amount of a compound according to the present invention , social phobia, sleep disorder, ADHD, PTSD, OCD, impulsive disorder, personality disorder, schizotypal disorder, aggression, chronic pain, neuropathy, autism spectrum disorder, Huntington's chorea, sclerosis, multiple sclerosis, Alzheimer's disease It relates to a method of treating a patient in need thereof.

According to one embodiment, the compounds of the present invention are used for treatment.

The use of a compound according to the invention is for the treatment of epilepsy, bipolar disorder, migraine or schizophrenia, or in another embodiment psychosis, mania, stress related disorder, acute stress response, bipolar depression, major depressive disorder, anxiety, panic Treatment of seizures, social phobia, sleep disorder, ADHD, PTSD, OCD, impulsive disorder, personality disorder, schizotypal disorder, aggression, chronic pain, neuropathy, autism spectrum disorder, Huntington's chorea, sclerosis, multiple sclerosis, Alzheimer's disease it is for

In another embodiment, the compound of the present invention is for the manufacture of a medicament for treating epilepsy, fragility X syndrome, Engelmann's syndrome, bipolar disorder, migraine or schizophrenia, or in another embodiment psychosis, mania, stress related disorder , Acute Stress Response, Bipolar Depression, Major Depressive Disorder, Anxiety, Panic Attack, Social Phobia, Sleep Disorder, ADHD, PTSD, OCD, Impulsive Disorder, Personality Disorder, Schizotypal Disorder, Aggression, Chronic Pain, Neuropathy, Autism Spectrum For the manufacture of a medicament for treating disorders, Huntington's chorea, sclerosis, multiple sclerosis, Alzheimer's disease.

In this context, “optionally substituted” means that the indicated moiety may or may not be substituted and, when substituted, is mono- or di-substituted. When no substituent is indicated for an “optionally substituted” moiety, it is understood that the position is held by a hydrogen atom.

A given range may be indicated interchangeably with "-" (dash) or "between", for example, the term "C _1-3 alkyl" is equivalent to "C ₁ to C ₃ alkyl".

The terms "C ₁ -C ₃ alkyl" and "C ₁ -C ₆ alkyl" refer to unbranched or branched saturated hydrocarbons having from 1 to 6 (inclusive) carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl and t-butyl.

The term “C ₁ -C ₃ alkoxy” refers to a moiety of the formula —OR, wherein R represents C ₁ -C ₃ alkyl as defined above.

The term “C ₃ -C ₄ cycloalkyl,” “C ₃ -C ₅ cycloalkyl,” “C ₃ -C ₈ cycloalkyl,” or “cyclopropyl,” refers to a saturated monocyclic ring. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Route of administration:

Pharmaceutical compositions comprising a compound of the present invention as defined above may be administered by any suitable route, such as oral, rectal, nasal, buccal, sublingual, transdermal and parenteral (eg subcutaneous, intramuscular and intravenous) routes. It may be formulated specifically for administration, the oral route being preferred.

It will be understood that the route will vary depending on the general condition and age of the subject being treated, the nature of the disease being treated and the active ingredient.

Pharmaceutical Formulations and Excipients:

In the following, the term "excipient" or "pharmaceutically acceptable excipient" refers to, by way of non-limiting example, fillers, anti-adherents, binders, coatings, colorants, disintegrants, flavoring agents, glidants, lubricants, preservatives, sorbents, sweeteners, Refers to pharmaceutical excipients including solvents, vehicles and adjuvants.

The present invention also provides a pharmaceutical composition comprising a compound according to the present invention, such as one of the compounds disclosed in the experimental section herein. The present invention also provides a process for preparing a pharmaceutical composition comprising a compound according to the present invention. The pharmaceutical composition according to the present invention is a pharmaceutical composition according to conventional techniques, such as disclosed in Remington, "The Science and Practice of Pharmacy", 22 ^th edition (2012), Edited by Allen, Loyd V., Jr. It can be formulated with acceptable excipients.

Pharmaceutical compositions for oral administration include solid oral dosage forms such as tablets, capsules, powders and granules; and liquid oral dosage forms such as solutions, emulsions, suspensions and syrups, as well as powders and granules dissolved or suspended in suitable liquids.

Solid oral dosage forms may be presented as discrete units (eg, tablets or hard or soft capsules) each containing a predetermined amount of the active ingredient and preferably one or more suitable excipients. Where appropriate, solid dosage forms may be prepared by coatings such as enteric coatings, or they may be formulated to provide modified release of the active ingredient, such as sustained or sustained release, according to methods well known in the art. Where appropriate, the solid dosage form may be a dosage form that disintegrates in saliva, such as, for example, an orally disintegrating tablet.

Examples of excipients suitable for solid oral dosage forms include microcrystalline cellulose, corn starch, lactose, mannitol, povidone, croscarmellose sodium, sucrose, cyclodextrin, talcum, gelatin, pectin, magnesium stearate, stearic acid and lower alkyls of cellulose. ethers, but are not limited thereto. Similarly, solid dosage forms may include excipients for sustained or sustained release dosage forms known in the art, such as glyceryl monostearate or hypromellose. If solid materials are used for oral administration, the dosage form can be prepared, for example, by mixing the active ingredient with a solid excipient and subsequently compressing the mixture in a conventional tabletting machine, or the dosage form can be prepared, for example, into a hard capsule, for example It may be in the form of a powder, pellets or mini-tablets. The amount of solid excipient will vary widely, but will typically range from about 25 mg to about 1 g per dosage unit.

Liquid oral dosage forms may be presented, for example, as elixirs, syrups, oral drops or liquid-filled capsules. Liquid oral dosage forms may also be presented as powders for solution or suspension in aqueous or non-aqueous liquids. Examples of excipients suitable for liquid oral formulations include ethanol, propylene glycol, glycerol, polyethylene glycol, poloxamers, sorbitol, poly-sorbates, mono and diglycerides, cyclodextrins, coconut oil, palm oil and water, It is not limited to these. Liquid oral dosage forms can be prepared, for example, by dissolving or suspending the active ingredient in an aqueous or non-aqueous liquid, or incorporating the active ingredient into an oil-in-water or water-in-oil liquid emulsion.

Additional excipients, such as colorants, flavorings and preservatives, and the like, may be used in solid and liquid oral formulations.

Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous solutions, dispersions, suspensions or emulsions for injection or infusion, concentrates for injection or infusion, as well as sterile solutions or dispersions reconstituted in sterile solutions or dispersions for injection or infusion prior to use. contains powder. Examples of excipients suitable for parenteral formulations include, but are not limited to, solutions of water, coconut oil, palm oil, and cyclodextrin. Aqueous formulations should be suitably buffered and isotonic with sufficient saline or glucose, if necessary.

Other types of pharmaceutical compositions include suppositories, inhalants, creams, gels, dermal patches, implants, and formulations for buccal or sublingual administration.

It is essential that the excipients used in any pharmaceutical formulation are compatible with the intended route of administration and are compatible with the active ingredient.

Volume:

In one embodiment, the compound of the present invention is administered in an amount from about 0.001 mg/kg body weight to about 100 mg/kg body weight daily. In particular, the daily dosage may range from 0.01 mg/kg body weight to about 50 mg/kg body weight daily. The exact dosage will depend on the frequency and mode of administration, the sex, age, weight and general condition of the subject being treated, the nature and severity of the disease being treated, any comorbidity being treated, the desired therapeutic effect and other factors known to those skilled in the art. It will be different.

A typical oral dosage for adults will be in the range of 0.1 to 1000 mg/day of a compound of the invention, such as 1 to 500 mg/day, such as 1 to 100 mg/day or 1 to 50 mg/day. Conveniently, the compound of the present invention is administered in unit dosage form containing the compound of the present invention in an amount of about 0.1 to 500 mg, such as 10 mg, 50 mg 100 mg, 150 mg, 200 mg or 250 mg of said compound. .

Isomeric and tautomeric forms:

When a compound of the present invention contains one or more chiral atoms, reference to the compound shall cover enantiomerically or diastereomerically pure compounds as well as mixtures of enantiomers or diastereomers in any ratio, unless otherwise stated. .

The MDL enhanced stereo representation is used to describe the unknown stereochemistry of the compounds of the present invention. Therefore, the label of "or1" at a chiral carbon atom is such that it indicates that the absolute conformation at this atom is not known, for example, that the conformation at this carbon atom is either (S) or (R). used

Moreover, a chiral bond from a carbon atom labeled "or1" using an upward wedge or a downward wedge is the same expression, for example the two figures have the same meaning, which means that it is labeled "or1" The absolute conformation at the carbon atom is not known and may be (S) or (R).

As such, the use of an upwardly wedged bond and a downward wedged bond from the atom labeled "or1" is simply intended to provide a visual clue that the figures represent different stereoisomers, wherein the carbon atom labeled "or1" The three-dimensional structure in is not known.

Moreover, some of the compounds of the present invention may exist in different tautomeric forms, and it is intended that any tautomeric forms that these compounds can form are included within the scope of the present invention.

A therapeutically effective amount:

In the present context, the term "therapeutically effective amount" of a compound refers to alleviating, arresting, partially arresting, eliminating, , means an amount sufficient to delay. An amount suitable to achieve this is defined as a “therapeutically effective amount”. An effective amount for each purpose will vary depending on the severity of the disease or injury as well as the weight and general condition of the subject. It will be appreciated that the determination of an appropriate dosage may be accomplished using routine experimentation by constructing a matrix of values and testing for differences in the matrix, all within the ordinary skill of a trained physician.

TREATMENT AND TREATMENT:

In this context, "treatment" or "treating" is intended to refer to the care and protection of a patient for the purpose of alleviating, arresting, partially arresting, eliminating, or delaying the progression of clinical signs of disease. do. The patient to be treated is preferably a mammal, in particular a human.

All references, including publications, patent applications, and patents, cited herein are set forth in their entirety (to the maximum extent permitted by law) and individually and specifically indicated that each reference is incorporated by reference. To the same extent as if it were incorporated herein by reference in its entirety.

Use in epilepsy, epileptic syndrome, epileptic symptoms or seizures

In another embodiment, the present invention requires treatment suffering from epilepsy, epileptic syndrome, epileptic symptoms, treatment-resistant or refractory epilepsy, or seizures comprising administering to a subject a therapeutically effective amount of a compound according to the present invention. It's about how to treat patients.

In another embodiment, the present invention provides focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures comprising administering to a subject a therapeutically effective amount of a compound of the present invention; Generalized idiopathic epilepsy, grand seizures, superimposed epilepsy, neonatal seizures, KCNQ epileptic encephalopathy (KCNQ2EE) and benign familial neonatal convulsions and other epileptic syndromes (e.g., severe myoclonic epilepsy in infants, epilepsy with continuous spikes during slow wave sleep) , West Syndrome, Lennox-Gastaut Syndrome, Dravette Syndrome and Premature Myoclonic Encephalopathy Otahara Syndrome), or stress, hormonal changes, drugs (such as amphetamine or cocaine), alcohol, infection, or metabolic disorders (such as hyponatremia) ) or for use in the treatment of neurodegenerative disorders such as Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, epileptic conditions as part of frontotemporal degeneration it's about

The use of the compounds according to the invention is for focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, generalized idiopathic epilepsy, grand seizures, superimposition of epilepsy, neonatal seizures, KCNQ epileptic encephalopathy ( KCNQ2EE) and benign familial neonatal convulsions and other epileptic syndromes (e.g., severe myoclonic epilepsy in infants, epilepsy with continuous spikes during slow wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravette syndrome and premature myoclonic encephalopathy) epilepsy, including use in the treatment of stress-related seizures, hormonal changes, drugs, alcohol, infection, traumatic brain injury, stroke, brain cancer, autism spectrum disorders or metabolic disorders (eg, hyponatremia) or for the treatment of neurodegenerative disorders such as Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, epileptic syndrome as part of frontotemporal degeneration.

In another embodiment, the compound of the present invention comprises epilepsy, epileptic syndrome, epileptic condition, treatment-resistant or refractory epilepsy, or focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures. , generalized idiopathic epilepsy, grandiose seizures, superimposed epilepsy, neonatal seizures, KCNQ epileptic encephalopathy (KCNQ2EE) and benign familial neonatal convulsions and other epileptic syndromes (e.g., severe myoclonic epilepsy in infants, with continuous spikes during slow wave sleep). epilepsy, West syndrome, Lennox-Gastaut syndrome, Dravette syndrome and premature myoclonic encephalopathy (Otahara syndrome), or stress-related seizures, hormonal changes, drugs, alcohol, infection, traumatic brain injury, stroke, brain cancer, autism spectrum disorder or for the manufacture of a medicament for treating seizures, including metabolic disorders (eg hyponatremia) or of epileptic conditions as part of neurodegenerative disorders such as Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, frontotemporal degeneration. for use in treatment.

The classification of epilepsy can be based on ICD-10 (2016, published by WHO), described in sections G40 and G41, and is included in the treatment of epilepsy according to the present invention.

G40.0 Epilepsy syndrome with localization-related (localized) (partial) idiopathic epilepsy and seizures of localization onset

G40.1 Epilepsy syndrome with localization-related (localized) (partial) symptomatic epilepsy and simple partial seizures

G40.2 Epilepsy syndrome with localization-related (localized) (partial) symptomatic epilepsy and complex partial seizures

G40.3 Systemic idiopathic epilepsy and epileptic syndrome

G40.4 Other systemic epilepsy and epileptic syndromes

G40.5 Special interstitial syndrome

G40.6 Grand seizures, unspecified (with or without minor seizures)

G40.7 Minor seizures, unspecified, without major seizures

G40.8 Other epilepsy

G40.9 Epilepsy, unspecified

G41 superlative epilepsy

treatment of seizures

A seizure is a sudden, uncontrolled electrical disturbance in the brain. This can result in changes in behavior, movement or emotion, and perceptual levels. When a person has a tendency to have two or more seizures or recurrent seizures, it is diagnosed as epilepsy.

There are many types of seizures that vary in severity. The types of seizures vary depending on where and how they occur in the brain. Most seizures last between 30 seconds and 2 minutes.

focal seizures

Local seizures result from abnormal electrical activity in one brain region. Localized seizures may occur with or without sensory loss:

· Focal seizures with impaired consciousness. These seizures are accompanied by a change or loss of perception or consciousness. A person can see into space, and can usually not respond to the environment or perform repetitive movements such as hand rubbing, chewing, swallowing, or walking in circles.

· Focal seizures without paresthesia. These seizures can change emotions or the way objects look, smell, feel, taste, and sound, but the person does not lose perception. These seizures can also produce unintentional jerking of body parts such as arms or legs, and spontaneous sensory syndromes such as tingling, dizziness and flashing lights.

generalized seizures

Seizures involving all brain regions are called generalized seizures. The different types of generalized seizures include:

· Absence seizures. Absence seizures, formerly known as minor seizures, usually occur in children and are characterized by seeing in the air or elusive body movements such as blinking or dabbing in the mouth. These seizures occur in clusters and can cause brief loss of consciousness.

· Tension seizures. Tonic seizures cause muscle stiffness. These seizures usually affect the muscles in the back, arms, and legs.

· Atonic seizures. Atonic seizures, also known as akinetic seizures, cause sudden collapse or loss of muscle control that can lead to a fall.

· Myoclonic seizures. Myoclonic seizures are associated with repetitive or pulsatile, jerking muscle movements. These seizures usually affect the neck, face, and arms.

· Myoclonic epilepsy. Myoclonic epilepsy usually results from sudden brief jerking or convulsions in the arms and legs.

· Tonic-clonic seizures. Tonic-clonic seizures, previously known as grand seizures, are the most dramatic type of epileptic seizures and can cause sudden loss of perception, stiffness and tremors, and sometimes loss of bladder control or tongue biting.

In many cases, seizures can be associated with or caused by:

High fever, which may be associated with an infection, such as meningitis

lack of sleep

Low sodium in the blood (hyponatremia), which may be caused by treatment with a diuretic

Medications such as certain pain relievers, antidepressants, or smoking cessation medications that lower the seizure threshold

Head trauma causing bleeding sites in the brain

stroke

brain tumor

Drugs such as amphetamines or cocaine

Alcohol

Headings and subheadings are used herein for convenience only and should not be construed as limiting the invention in any way.

The use of any and all embodiments or exemplary language (including "for example," "for example," "for example," and "such as") herein is merely intended to better exemplify the invention. It is intended and does not impose a limitation on the scope of the present invention unless otherwise indicated.

The citation and inclusion of patent documents herein is made for convenience only and does not reflect any aspect of the validity, patentability and/or enforceability of such patent documents.

This invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law.

experimental section

Biological Assessment:

cell culture

Synthesized cDNA fragments encoding human Kv7.3 and human Kv7.2 separated by P2A sequence using BamHI and XhoI restriction sites were inserted into pcDNA5/FRT/TO vector. The constructs were then transfected into HEK Flp-In 293 cells using Lipofectamine2000. Transfected cells were grown for 48 hours in DMEM containing 10% (v/v) FBS and 1% PenStrep followed by 10% (v/v) FBS at 37° C. in a humidified atmosphere of 5% CO ₂ , kept under selection in DMEM containing 1% PenStrep and 200 ug/mL of hygromycin B. The resulting stable hKv7.2/hKv7.3 cell line (HEK-hKv7.2/hKv7.3) was functionally tested with an automated whole-cell patch-clamp and was sensitive to XE991 and translocated by retigabine to conventional Kv7- current was indicated.

Thallium Ingress Assay

Thallium uptake assays for potassium channel activation were performed analogously to published procedures using the FLIPR Potassium Assay kit (Molecular Devices) (C.D. Weaver, et al., J Biomol Screen 2004, 9, 671-677). HEK-hKv7.2/hKv7.3 at a density of 80,000 cells/well (100 μl/well) if cells are analyzed the next day or 40,000 cells/well (100 μl/well) if cells are analyzed 2 days after seeding Cells were plated in 96 well, black wall, clear bottom culture plates (Corning, Acton, MA).

On the day of the assay, the medium was removed, then 50 uL/well of test compound was diluted to 2x final concentration in HBSS containing 20 mM HEPES, and 50 uL/well of 2x dye load buffer was added. The cells were then incubated for 60 min at room temperature in the dark. Chloride-free stimulation buffer containing Tl ⁺ and K ⁺ at 5x final concentration (5x concentration: 5 mM in both cases) and test compound at 1x final concentration were prepared during incubation. Then, the cells were analyzed on the FDSS7000EX Functional Drug Screening System (Hamamatsu). After 60 s of the reference fluorescence signal read at 0.1 Hz and after 10 s at 1 Hz, 25 uL/well of stimulation buffer is added and fluorescence continues for 50 s at 1 Hz followed by 4 min at 0.1 Hz. was measured. Compound effects were quantified using AUC as readout and normalized to the reference compound contained in each plate.

compound effect

In the assays described above, the compounds of the present invention had the following biological activities:

Synthesis of compounds of the present invention:

General method:

General procedures for the synthesis of intermediates and compounds of general formula I are described in Scheme 1 and are specifically exemplified in the preparations and examples. Variations of the described procedures known to those skilled in the art are within the scope of the present invention.

Compounds of the present invention are prepared as described in Scheme 1. Some of the compounds of formula I contain two chiral carbon atoms and are formed as mixtures of diastereomers. If this is the case, the diastereomers can be separated to give the single stereoisomers Ia and Ib.

Scheme 1 :

Scheme I depicts the preparation of compounds of general formula I by two general routes. The first route is the synthesis of compounds of formula (I) by reaction of an enantiomerically pure amine of formula (II) and an acid of formula (III) via methodologies well known in the art for the conversion of acids and amines to amides. This methodology includes, by way of non-limiting example, the formation of reactive derivatives of acids of formula III, including activated esters and reactive mixed anhydrides, followed by condensation with amines of formula II. One such methodology is (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexa The condensation is carried out in the presence of a suitable base such as fluorophosphate (HATU) and diisopropylethylamine (DIPEA).

Alternatively, when R ² is H, compounds of general formula I can be prepared via the second general route wherein the intermediate of general formula V is treated with a suitable reducing agent such as NaBH ₄ in a suitable solvent such as methanol. Intermediates of formula (V) can be obtained from enantiomerically pure amines of formula (II) and carboxylic acids of formula (IV) (R = H). This transformation can be carried out using similar reaction conditions as described above for the condensation of II and III to form I.

A variant of this procedure is a direct coupling reaction between a chiral amine of general formula II and a carboxylic acid ester of general formula IV (R = Me, Et). This reaction can be carried out by heating the reactants to reflux in a suitable solvent such as toluene in the presence of a suitable base such as DIPEA and in the presence of a catalytic amount of a suitable catalyst such as 4-dimethylamino pyridine (DMAP).

Optically active amines of formula II can be prepared as outlined in Scheme 2a:

Scheme 2a :

The aldehydes of formula VI may be condensed with ( R )-2-methylpropane-2-sulfinamide in a suitable solvent such as dichloroethane in the presence of a drying agent such as titanium(IV) isopropoxide or copper sulfate. The sulfinyl imine XV formed is treated with R ³ MgBr in a suitable inert solvent such as THF to provide the corresponding substituted ( R )-2-methyl- N -(( S )-1-aryl-alkyl)propane-2-sulfinamide VII is formed, which is converted to a compound of formula II by treatment with a suitable acid in a suitable solvent such as HCl in MeOH.

In variations of this procedure, the R ³ substituent bearing a functional group may be further modified by standard functional group conversion methodologies known to chemists skilled in the art. An example of such a manipulation for the preparation of a chiral amine is illustrated in Scheme 2b. An intermediate of general formula VII (where R ³ =allyl) can be formed from XV and allyl-MgBr, using H ₂ (g) in the presence of a suitable catalyst such as Pd/C in a suitable solvent such as ethyl acetate R ³ = can undergo catalytic reduction to n-propyl. Alternatively, the intermediate of formula VII, wherein R ³ =allyl, undergoes di-hydroxylation followed by oxidative cleavage to a suitable solvent such as 2,6-lutidine in a suitable solvent such as dioxane/H ₂ O. Intermediate VII, where R ³ =acetaldehyde, can be produced by treatment with a suitable catalyst such as K ₂ OsO ₄ and NaIO ₄ in the presence of a base. The aldehyde obtained is subjected to further transformation; The exchange of oxygen for two fluorine atoms can be effected, for example, by treatment with a suitable reagent such as (diethylamino)sulfur trifluoride (DAST) in a suitable solvent such as DCM. In a final step, the chiral amine can be obtained by hydrolysis as described above.

As another example, an intermediate of general formula XVI, wherein R ³ is an acetic acid ester, can be formed from XV in reaction with ethyl 2-bromo acetate in the presence of CuCl and activated Zn in a suitable solvent such as THF. . Ester groups can be further derivatized by transformations known to the skilled chemist. For example, the ester can be reduced to a primary alcohol by treatment with a suitable reducing agent such as LiAlH ₄ in a suitable solvent such as THF. The alcohol obtained can also be further derivatized via transformations known to the skilled person. For example, an alcohol may be converted to a leaving group via activation with a reagent such as mesyl chloride in the presence of a suitable base such as triethylamine (TEA) in a suitable solvent such as DCM. The resulting mesylate can be reacted with a suitable nucleophile such as potassium cyanide in a suitable solvent such as DMSO.

Scheme 2b:

Aldehydes of general formula VI can also be converted to chiral amines of general formula II via an alternative strategy, such as illustrated in Scheme 2c:

Scheme 2c:

After this procedure, the suitably substituted benzaldehyde VI can be converted to the corresponding suitably substituted styrene using the Wittig methodology known to the skilled chemist. This intermediate can undergo an alkylation-oxidation reaction to form the keto-intermediate XVII. Intermediates of formula XVII may be condensed with ( R )-2-methylpropane-2-sulfinamide in a suitable solvent such as dichloroethane in the presence of a suitable desiccant such as titanium(IV) ethoxide. The sulfinyl imine formed can be reduced with a suitable reducing agent such as L-selectride in a suitable inert solvent such as THF, such that the correspondingly suitably substituted ( R )-2-methyl- N -(( S )-1- Giving the aryl-alkyl)propane-2-sulfinamide, which can be converted to the chiral amine of general formula II by treatment with a suitable acid in a suitable solvent such as HCl in MeOH.

Those skilled in the art will recognize that other transformations from several intermediates are possible, and the present invention is intended to cover such alternative transformations.

The aldehydes of formula VI used to prepare the compounds of the present invention are commercially available and can be prepared as described in the literature, and are described in Journal of Medicinal Chemistry, 45(18), 3891-3904; 2002].

In another procedure, the intermediate sulfinyl imine obtained from the reaction of a chiral amine of formula II with ( R )-2-methylpropane-2-sulfinamide with a reagent such as L-selectride as shown in Scheme 3a It can be obtained from aryl ketones via hydride reduction.

Scheme 3a :

A variant of this procedure is illustrated in Scheme 3b. In this procedure, an additional R ³ substituent which is an ether can be placed from the consensus alpha bromoacetophenone intermediate XI obtained by bromination of a suitably substituted acetophenone. Examples include, but are not limited to, introduction of a fluoroalkyl methylene ether group into R ³ . As such, using this methodology, a suitably substituted bromoacetophenone can be further converted to a chiral amine as described above by Finkel in a suitable solvent such as dimethylacetamide (DMA) to yield intermediate XII. It can be reacted with fluoroalkoxy donors such as trifluoromethyl trifluoromethanesulfonate and KF under Finkelstein conditions. Other examples include, but are not limited to, the introduction of alkyl methylene ethers as R ³ . As such, suitably substituted bromoacetophenones can be prepared with 4-methyl- in a suitable solvent such as THF in the presence of a suitable base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). It can be converted to the acyl diazo intermediate XIII by reaction with N'-(p-tolylsulfonyl)benzenesulfonohydrazide. Intermediate XIII may undergo a carbene-forming reaction by treatment with a suitable catalyst such as indium triflate in a suitable solvent such as toluene. The carbene formed can be captured in situ with a suitable alcohol to generate the alkoxy keto intermediate XIV . From intermediate XIV , the chiral amine of formula II can be obtained through standard manipulations as described above.

Scheme 3b:

Suitably substituted ketones or acetophenones used to prepare the compounds of the present invention are commercially available or can be prepared by methods known to those skilled in the art.

Those skilled in the art will recognize that other transformations from intermediates of formula XI are possible, and the present invention is intended to cover such alternative transformations.

Another suitable procedure for accessing chiral amines of general formula II, wherein R ³ is ether, is outlined in Scheme 4.

Scheme 4:

In this procedure, the glyoxylate sulfinyl imine formed in the condensation reaction between the glyoxylic acid ester and ( R )-2-methylpropane-2-sulfinamide is bis-oxygen in a suitable solvent such as dioxane as described in JP 2017/095366A. The reaction with the appropriately substituted boronic acid can be accomplished using a suitable catalyst such as (acetonitrile)(1,5-cyclooctadiene)rhodium(I) tetra-fluoroborate. The resulting intermediate VIII can be hydrolyzed to give an alcohol intermediate of general formula IX, reprotected with a suitable protecting group such as Boc under standard conditions, and subjected to ester reduction under suitable conditions such as LiAlH ₄ in THF. Intermediates of formula (IX) may be further derivatized to access the desired R ³ substituents. For example, the alcohol group in Intermediate IX is difluoromethylated using a suitable reagent such as 2,2-difluoro-2-(fluorosulfonyl)acetic acid under conditions such as CuI activation in a suitable solvent such as acetonitrile. Alternatively, the alcohol group in IX may be alkylated using a simple alkyl halide such as methyl iodide in the presence of a suitable base such as NaH in a suitable solvent such as THF. Alternatively, the alcohol of Intermediate IX can be converted to a leaving group via activation with a reagent such as mesyl chloride in the presence of a suitable base such as TEA in a suitable solvent such as DCM. The resulting mesylate can be reacted with a suitable nucleophile such as potassium cyanide in a suitable solvent such as DMSO.

Those skilled in the art will recognize that other transformations from intermediates of formula IX are possible, and the present invention is intended to cover such alternative transformations.

Carboxylic acids of formula III can be prepared as outlined in Scheme 5:

Scheme 5 :

Ketones of general formula X are reacted with alkyl esters of bromoacetic acid activated for example with Zn and iodine to form the corresponding aldol adducts. In an alternative procedure, the bromoacetic acid ester can be activated using Zn and TMSCl (trimethylsilyl chloride). In a final step, hydrolysis of the alkyl ester is achieved by treatment with an appropriate base such as NaOH or LiOH in a suitable solvent such as water or an alcohol in water, followed by acidification with a suitable acid to yield a compound of formula III .

Carboxylic acid esters of formula IV (R = Me, Et) are commercially available or can be prepared as outlined in Scheme 6:

Scheme 6 :

A suitably substituted carboxylic acid can be activated using a suitable reagent such as CDI to give an intermediate of formula IV and condensed with potassium 3-ethoxy-3-oxo-propanoate in the presence of MgCl ₂ .

¹ H NMR spectra were recorded at 400.13 MHz on a Bruker Avance III 400 instrument or at 300.13 MHz on a Bruker Avance 300 instrument. Deuterated dimethyl sulfoxide or deuterated chloroform was used as solvent. Tetramethylsilane was used as an internal reference standard. Chemical shift values are expressed in ppm-values relative to tetramethylsilane. The following abbreviations are used for the multiplicity of NMR signals: s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet, h = hexant, dd = doublet, ddd = double doublet, dt = double triplet, dq = double quartet, tt = triplet of triplet, m = multiplet and brs = broad singlet.

Chromatographic systems and methods for evaluating chemical purity (LCMS methods) and chiral purity (SFC and HPLC methods) are described below.

Chiral analysis method:

Preparation of intermediates :

IIb: (( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine

Step 1: Preparation of ethyl 2-[( R ) -tert -butylsulfinyl]imino acetate

To a solution of ethyl 2-oxoacetate (7.5 g, 36.7 mmol) and ( R )-2-methylpropane-2-sulfinamide (4.9 g, 40.4 mmol) in DCM (150 mL) CuSO ₄ (12.9 g, 80.8 mmol) ) was added and the reaction mixture was stirred at 25° C. for 24 h. The solid was filtered, washed with ethyl acetate (50 mL), the organic phases were combined and concentrated. The resulting residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate, 5/1) to give the desired product (5.1 g, 67.6% yield).

Step 2: Preparation of ethyl ( 2R)-2-[[(R ) -tert -butylsulfinyl]amino]-2-[3-(trifluoromethoxy)phenyl]acetate

Ethyl-2-[( R )-tert-butylsulfinyl] iminoacetate (7 g, 34.1 mmol) and [3-(trifluoromethoxy)phenyl]boronic acid (8.4 g, 40.9 mmol) was added [Rh(COD)(MeCN) ₂ ]BF ₄ (1.3 g, 3.4 mmol), and the mixture was stirred at 80° C. for 16 h. The product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 5:1) to give 9.8 g (78%).

Step 3: Preparation of ethyl (2 R )-2-amino-2-[3-(trifluoro-methoxy)phenyl]acetate hydrochloride

Ethyl ( 2R)-2-[[(R ) -tert-butylsulfinyl]amino]-2-[3-(trifluoromethoxy)phenyl]acetate (9.8 g, 26.7 mmol) in MeOH (100 mL) HCl/MeOH (4 M , 100 mL) was added to a solution of Romethoxy)phenyl]acetate (7.8 g, crude) was obtained.

Step 4: Preparation of ethyl ( R )-2-(( tert -butoxycarbonyl)amino)-2-(3-(difluoromethoxy)phenyl)acetate

NaHCO _{3 (} 1.7 g) was added and stirred at 25° C. for 16 h. The mixture was concentrated and purified by chromatography on silica (petroleum ether: ethyl acetate = 10:1) to give the product (7.2 g).

Step 5: Preparation of tert -butyl ( R )-(1-(3-(difluoromethoxy)phenyl)-2-hydroxyethyl)carbamate

To a suspension of LiAlH ₄ (1.7 g) in THF (200 mL) with ice cooling ethyl ( R )-2-(( tert -butoxycarbonyl)amino)-2-(3-(di Fluoromethoxy)phenyl)acetate (4 g) was added. The reaction was allowed to warm to 25° C. and stirred for 2 h. Anhydrous magnesium sulfate was added, followed by successive additions of water and one drop of ethyl acetate. The insoluble material was filtered through a pad of Celite. The filtrate was concentrated and purified by chromatography on silica (petroleum ether: ethyl acetate = 5:1) (2.1 g).

Step 6: Preparation of tert- butyl (R )-(2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate

To a solution of tert -butyl ( R )-(1-(3-(difluoromethoxy)phenyl)-2-hydroxyethyl)carbamate (1.5 g) in MeCN (20 mL) was added CuI (360 mg) and stirred at 25° C. for 30 minutes under N ₂ atmosphere. A solution of 2,2-difluoro-2-fluorosulfonyl-acetic acid (1.7 g) in MeCN (5 mL) was added at 45° C. over 30 min and the reaction stirred at 45° C. for 1 h. The mixture was concentrated, then diluted with ethyl acetate (100 mL), filtered and concentrated to give the desired product (1.5 g, crude).

Step 7: Preparation of ( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine

To a solution of tert- butyl (R )-(2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate (1.5 g) in MeOH (15 mL) at 25 °C of HCl/MeOH (4 M in MeOH, 30 mL) was added and the reaction stirred at 25° C. for 30 min. Ammonium hydroxide (30%) was added to pH = 9, the solution was concentrated and purified by chromatography on silica (petroleum ether: ethyl acetate = 2:1) ( R )-2-(difluoromethoxy) -1-(3-(trifluoromethoxy)phenyl)ethan-1-amine (700 mg) was obtained.

IIa: ( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethan-1-amine hydrochloride

Prepared as described for IIb using appropriate reagents.

IIc: ( R )-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethan-1-amine hydrochloride

Step 1: Preparation of 4-methyl-N'-(p-tolylsulfonyl)benzene sulfonohydrazide

To a mixture of 4-methylbenzenesulfonohydrazide (70 g) and 4-methylbenzenesulfonyl chloride (93 g) was added DCM (400 mL). The mixture was cooled to 0° C., pyridine (38.65 g) was added dropwise, and the reaction mixture was stirred at 0° C. for 1 hour and at 20° C. for 7 hours. The mixture was added to water (200 mL) and methyl-tert-butyl ether (METB) (200 mL) and filtered. The filter cake was washed with METB (200 mL) and dried to give 4-methyl-N'-(p-tolylsulfonyl)benzenesulfonohydrazide (125 g).

1H NMR (DMSO-d6 400MHz): δ 9.55 (s, 2H), 7.61 (d, 4H), 7.35 (d, 4H), 2.36 (s, 6H).

Step 2: Preparation of 2-bromo-1- (3- (difluoromethoxy) phenyl) ethan-1-one

To a solution of 1-[3-(difluoromethoxy)phenyl]ethanone (10 g) in dioxane (100 mL) was added a solution of Br ₂ (8.58 g) in dioxane (100 mL). The resulting mixture was stirred at 20° C. for 2 h. Saturated aqueous NaHCO ₃ solution (50 mL) and H ₂ O (100 mL) were added and the aqueous phase was extracted with EtOAc (200 mL×2). The organic phase was washed with brine (200 mL), dried over Na ₂ SO ₄ and concentrated to give 2-bromo-1-[3-(difluoromethoxy)phenyl]ethanone (17 g).

1H NMR (CDCl3 400MHz): δ 7.81 (d, 1H), 7.72 (s, 1H), 7.49 (t, 1H), 7.37 (d, 1H), 6.56 (t, 1H), 4.41 (s, 2H).

Step 3: Preparation of 1-(3-(difluoromethoxy)phenyl)-2-iminoethan-1-one

2-Bromo-1-[3-(difluoromethoxy)phenyl]ethanone (5.6 g) and 4-methyl-N′-(p-tolylsulfonyl)benzenesulfonohydra in THF (100 mL) To a solution of zid (11.51 g) was added DBU (12.87 g) dropwise at 0°C. The reaction mixture was stirred at 0° C. for 1 h and at 20° C. for 4 h. The mixture was quenched with saturated aqueous NaHCO ₃ (200 mL), diluted with water (200 mL), then extracted with EtOAc (200 mL×2). The organic layer was washed with brine (100 mL), dried over Na ₂ SO ₄ and concentrated. The crude was purified by column chromatography on silica gel (20% EtOAc in petroleum ether) to give 1-(3-(difluoromethoxy)phenyl)-2-iminoethan-1-one (6.4 g) made it

1H NMR (CDCl ₃ , 400 MHz): δ 7.57 (dt, 1H), 7.55 (s, 1H), 7.46 (t, 1H), 7.31 (dd, 1H), 6.56 (t, 1H), 5.90 (s, 1H) ).

Step 4: Preparation of 2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethan-1-one

To a solution of cyclopropanol (1.75 g) and 2-diazo-1-[3-(difluoromethoxy)phenyl]ethanone (3.2 g) in toluene (50 mL) under N ₂ indium(III) triflate ( 1.7 g) was added. The resulting mixture was stirred at 20° C. for 16 h. The mixture was quenched with saturated aqueous NaHCO ₃ (100 mL), diluted with H ₂ O (50 mL), then extracted with EtOAc (100 mL×2). The organic layer was washed with brine (200 mL×2), dried over Na ₂ SO ₄ and concentrated. The crude was purified by column chromatography on silica gel (5% EtOAc in petroleum ether) to give 2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethan-1-one (6.1 g) created

1H NMR (CDCl ₃ , 400 MHz): δ 7.76 (d, 1H), 7.68 (s, 1H), 7.47 (t, 1H), 7.34 (d, 1H), 6.55 (t, 1H), 4.74 (s, 1H) ), 3.55-3.50 (m, 1H), 0.70-0.66 (m, 2H), 0.53-0.49 (m, 2H).

Step 5: Preparation of ( R , Z ) -N-(2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethylidene)-2-methylpropane-2-sulfinamide

2-(cyclopropoxy)-1-[3-(difluoromethoxy)phenyl]ethanone (6.1 g) and (R)-2-methylpropane-2-sulfinamide (4.6 g) in THF (100 mL) ) was added Ti(OEt) ₄ (11.5 g). The resulting mixture was stirred at 60° C. for 8 hours, then used directly in the next step.

Step 6: Preparation of ( R ) -N -(( R )-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide

(R, Z ) -N-(2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethylidene)-2-methylpropane-2- in THF (150 mL) from the previous step To the solution of sulfinamide was added dropwise a solution of L-selectride (1 M in THF, 50.36 mL) at -45°C. The mixture was stirred at -45° C. for 1 h, quenched with MeOH (100 mL) and H ₂ O (100 mL) and filtered over celite. The filtrate was extracted with EtOAc (200 mL×2) and the organic layer was washed with brine (200 mL×2), dried over Na ₂ SO ₄ and concentrated. The crude was purified by column chromatography on silica gel (30% to 50% EtOAc in petroleum ether) ( R ) -N -(( R )-2-cyclopropoxy-1-(3-(difluoromethyl) To give toxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (2.4 g).

Step 7: ( R )-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethan-1-amine Preparation of hydrochloride

( R ) -N -(( R )-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (0.46) in MeOH (10 mL) g) was added HCl/MeOH (10 mL). The resulting mixture was stirred at 20 °C for 1 h and concentrated (1 R )-2-(cyclopropoxy)-1-[3-(difluoromethoxy)phenyl]ethanamine hydrochloride (0.46 g, crude ) was created.

IId: ( R )-2-cyclopropoxy-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine hydrochloride

Prepared as described for IIc using 1-[3-(trifluoromethoxy)phenyl]ethanone as starting material.

IIe: ( R )-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethan-1-amine hydrochloride

Step 1: Preparation of 2-bromo-1-[3-(difluoromethoxy)phenyl]ethanone

To a solution of 1-[3-(difluoromethoxy)phenyl]ethanone (5 g) in dioxane (50 mL) was added a solution of Br2 (4.29 g) in dioxane (50 mL) at 20°C . The mixture was stirred at 20° C. for 1 h, then diluted with EtOAc (200 mL) and washed with water (100 mL×3). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by column of chromatography on silica gel (petroleum ether: EtOAc = 10:1) to give 2-bromo-1-[3-(difluoromethoxy)phenyl]ethanone (5 g). .

Step 2: Preparation of 1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethan-1-one

To a solution of KF (712 mg) in DMA (20 mL) at 0° C. was added trifluoromethyl trifluoromethanesulfonate (4.11 g). The reaction mixture was stirred in a sealed tube for 1 h, then 2-bromo-1-[3-(difluoromethoxy)phenyl]ethanone (2.5 g, 9.43 mmol) and KI (157 mg) were added at 0 °C. was added to this solution, brought to 20° C., and stirred for 16 hours. The mixture was diluted with EtOAc (100 mL) and washed with water (50 mL×3). Concentration of the organic phase gave the product, which was purified by acidic preparative HPLC (1.4 g).

1H NMR (CDCl ₃ 400 MHz): δ 7.72 (d, 1H), 7.66 (s, 1H), 7.51 (t, 1H), 7.40 (d, 1H), 6.56 (t1H), 5.13 (s, 2H).

19F NMR (CDCl ₃ 400 MHz): δ -61.11, -81.52, -81.71.

Step 3: Preparation of ( R ) -N- (1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethylidene)-2-methylpropane-2-sulfinamide

1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethan-1-one (900 mg), (R)-2-methylpropane-2-sulfine in THF (50 mL) A mixture of amide (606 mg) and Ti(OEt) ₄ (2.28 g) was stirred under N ₂ at 60° C. for 16 h. The product (1.2 g, crude) in THF (70 mL) was obtained and used directly in the next step.

Step 4: Preparation of ( R ) -N -(( R )-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-2-methylpropane-2-sulfinamide

( R ) -N- (1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethylidene)-2-methylpropane-2-sulfinamide (1.2) in THF (70 mL) g) was added L-selectride (1 M in THF, 3.86 mL) at -60°C. The mixture was stirred at −60° C. for 0.5 h, then diluted with EtOAc (100 mL) and washed with water (50 mL×3). The organic phase was dried, filtered and concentrated. The crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate = 5:1) ( R ) -N -(( R )-1-(3-(difluoromethoxy)phenyl)-2 -(trifluoromethoxy)ethyl)-2-methylpropane-2-sulfinamide (600 mg) was obtained.

1H NMR (CDCl ₃ 400 MHz): δ 7.37 (t, 1H), 7.20 (d, 1H), 7.12-7.09 (m, 2H), 6.50 (t, 1H), 4.75-4.72 (m, 1H), 4.20 -4.16 (m, 1H), 4.14-4.05 (m, 1H), 3.87 (s, 1H), 1.21 (s, 9H).

Step 5: Preparation of ( R )-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethan-1-amine hydrochloride

( R ) -N -(( R )-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-2-methylpropane-2-sulfine in MeOH (10 mL) To a solution of amide (600 mg) was added HCl/MeOH (4 M in MeOH, 8.0 mL). The mixture was stirred at 15 °C for 1 h, then concentrated to (( R )-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethan-1-amine hydrochloride ( 500 mg, crude).

¹ H NMR (CDCl ₃ 400 MHz): δ 9.17 (s, 3H), 7.40-7.31 (m, 4H), 6.55 (t, 1H), 4.58 (s, 1H), 4.46-4.42 (m, 1H), 4.33-4.29 (m, 1H).

IIf: ( R )-2-(trifluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine hydrochloride

Prepared as described for IIe using 1-[3-(trifluoromethoxy)phenyl]ethanone as starting material.

¹ H NMR (CDCl ₃ 400 MHz): δ 9.18 (s, 3H), 7.19-7.47 (m, 1H), 7.19-7.38 (m, 2H), 7.27 (s, 1H), 4.65 (s, 1H), 4.47-4.42 (m, 1H), 4.32-4.30 (m, 1H).

IIg: ( S )-1-(3-(difluoromethoxy)phenyl)butan-1-amine hydrochloride

Step 1: Preparation of ( R ) -N- (3-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide

To a solution of 3-(difluoromethoxy)benzaldehyde (3 g) and (R)-2-methylpropane-2-sulfinamide (2.54 g) in DCE (120 mL) was added CuSO ₄ (13.91 g) . The mixture was stirred at 55° C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 10:1) to give the product (3 g).

Step 2: Preparation of (R)-N-((S)-1-(3-(difluoromethoxy)phenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide

To a solution of ( R ) -N- (3-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide (1 g) in DCM (40 mL) at 0° C. in THF at 0° C. Parent) Magnesium (1 M solution in THF, 10.9 mL) was added slowly. The resulting mixture was stirred at 0° C. for 1 hour and at 25° C. for 2 hours. The reaction mixture was quenched by addition of saturated NH ₄ Cl (10 mL) at 0° C., then diluted with H ₂ O (50 mL) and extracted with DCM (40 mL×3). The combined organic phases were washed with H ₂ O (40 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 1:2) ( R ) -N -(( S )-1-(3-(difluoromethoxy) Phenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (580 mg) was obtained.

¹ H NMR (CDCl ₃ 400 MHz): δ 7.31 (t, 1H), 7.15 (d, 1H), 7.08 (s, 1H), 7.01 (d, 1H), 6.48 (t, 1H), 5.73-5.66 ( m, 1H), 5.19-5.15 (m, 2H), 4.46 (t, 1H), 3.65 (s, 1H), 2.59-2.54 (m, 1H), 2.46-2.38 (m, 1H), 1.19 (s, 9H).

Step 3: Preparation of ( R ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)butyl)-2-methylpropane-2-sulfinamide

( R ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide in EtOAc (20 mL) To a solution of (580 mg) was added Pd/C (0.4 g, 10% purity) under N ₂ . The suspension was degassed under vacuum and purged several times with H ₂ . The mixture was stirred under H ₂ (18 psi) at 25° C. for 0.5 h. The reaction mixture was filtered and concentrated to give ( R ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)butyl)-2-methylpropane-2-sulfinamide (560 mg).

Step 4: Preparation of ( S )-1-(3-(difluoromethoxy)phenyl)butan-1-amine hydrochloride

HCl in a solution of ( R ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)butyl)-2-methylpropane-2-sulfinamide (580 mg) in MeOH (8 mL) /MeOH (4 M, 3.1 mL) was added. The mixture was stirred at 25° C. for 3 h, then concentrated to give (1 S )-1-[3-(difluoromethoxy)phenyl]butan-1-amine hydrochloride (250 mg).

IIh: ( S )-1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutan-1-amine hydrochloride

Step 1: Preparation of 1-(difluoromethoxy)-3-vinyl-benzene

To a solution of methyl triphenylphosphonium iodide (7.05 g) in DME (50 mL) was added K ₂ CO ₃ (2.41 g). The resulting mixture was stirred at 20° C. for 1 hour, then 3-(difluoromethoxy)benzaldehyde (1.5 g) was added, and stirring was continued at 80° C. for 15 hours. The mixture was filtered and the filter cake was washed with petroleum ether (100 mL). The filtrate was concentrated and purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 10/1) to give 1-(difluoromethoxy)-3-vinyl-benzene (1.4 g) got it

¹ H NMR (CDCl ₃ 400 MHz): δ 7.32 (t, 1H), 7.25 (d, 1H), 7.16 (s, 1H), 7.01 (d, 1H), 6.70 (t, 1H), 6.52 (t, 1H) ), 5.77 (d, 1H), 5.32 (d, 1H).

Step 2: Preparation of 1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutan-1-one

1,1-Difluoro-2-iodo-ethane (1 g), 1-(difluoromethoxy)-3-vinyl-benzene (1.33 g), bis[( Z )- in ACN (20 mL) In a solution of 1-methyl-3-oxo-but-1-enoxy]copper (273 mg) and Ag ₂ SO ₄ (325 mg) Et ₃ N (527 mg) and tert -butyl hydroperoxide (TBHP) ( 2.01 g, 70% in water) was added. The resulting mixture was stirred at 80° C. for 24 hours. The reaction was quenched with saturated aqueous Na ₂ S ₂ O ₃ and extracted with DCM (10 mL×3). The organic phases were combined, washed with brine (5 mL×2), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 5/1) to 1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutane -1-one (300 mg) was obtained.

¹ H NMR (CDCl ₃ 400 MHz): δ 7.82 (d, 1H), 7.73 (s, 1H), 7.50 (t, 1H), 7.36 (d, 1H), 6.57 (t, 1H), 6.02 (tt, 1H) ), 3.18 (t, 2H), 2.35-2.27 (m, 2H).

Step 3: Preparation of ( S , E ) -N- (1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutylidene)-2-methylpropane-2-sulfinamide

1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutan-1-one (300 mg) and (R)-2-methylpropane-2-sulfinamide in THF (10 mL) (218 mg) was added Ti(OEt) ₄ (547 mg). The mixture was stirred at 60° C. for 6 hours. The reaction mixture was used directly in the next step.

Step 4: Preparation of N -[(1 S )-1-[3-(difluoromethoxy)phenyl]-4,4-difluoro-butyl]-2-methyl-propane-2-sulfinamide

L-Selectride (1 M in THF, 3.59 mL) was mixed with ( S ) -N- (1-(3-(difluoromethoxy)phenyl)-4,4-difluorobu in THF at -48°C. To a solution of thylidene)-2-methylpropane-2-sulfinamide (423 mg). The reaction mixture was stirred for 0.5 h, after which it was brought to 0° C. and H ₂ O (ca. 10 mL) was added. The resulting mixture was extracted with EtOAc (35 mL×2). The organic extracts were washed with brine (10 mL), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 1/1) to N -[(1 S )-1-[3-(difluoromethoxy)phenyl]- 4,4-Difluoro-butyl]-2-methyl-propane-2-sulfinamide (140 mg) was obtained.

Step 5: ( S )-1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutan-1-amine hydrochloride

N -[(1 S )-1-[3-(difluoromethoxy)phenyl]-4,4-difluoro-butyl]-2 in MeOH (10 mL) and HCl/MeOH (5 mL, 4M) -Methyl-propane-2-sulfinamide (140 mg) was stirred at 20° C. for 1 hour. The mixture was concentrated to give ( S )-1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutan-1-amine hydrochloride (110 mg).

II: (S)-1-(3-(difluoromethoxy)phenyl)-3,3-difluoropropan-1-amine hydrochloride

Step 1: Preparation of ( S , E ) -N- (3-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide

To a solution of 3-(difluoromethoxy)benzaldehyde (5 g) and ( R )-2-methylpropane-2-sulfinamide (4.22 g) in DCE (150 mL) was added CuSO ₄ (23 g) . The reaction mixture was stirred at 55° C. for 20 h, then filtered and concentrated. The crude product was purified by chromatography on silica (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 5/1) ( S , E ) -N- (3-(difluoromethoxy)benzylidene) -2-methylpropane-2-sulfinamide (6.9 g) was obtained.

¹ H NMR (CDCl ₃ 400 MHz): δ 8.55 (s, 1H), 7.65 (d, 1H), 7.62 (s, 1H), 7.47 (t, 1H), 7.25 (d, 1H), 6.55 (t, 1H), 1.25 (s, 9H).

Step 2: Preparation of ( S ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide

To a solution of ( S , E )-N-(3-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide (2 g) in DCM (60 mL) at 0° C. Parent) Magnesium (1 M solution in THF, 21.79 mL) was added slowly. The reaction mixture was stirred at 0° C. for 1 h and at 25° C. for 2 h. The reaction was quenched by addition of saturated aqueous NH ₄ Cl (10 mL) at 0° C., then diluted with H ₂ O (50 mL) and extracted with DCM (40 mL×3). The combined organic phases were washed with H ₂ O (40 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 1/2) to ( S ) -N -(( S )-1-(3-(difluoromethoxy)phenyl )But-3-en-1-yl)-2-methylpropane-2-sulfinamide (2.3 g) was obtained.

¹ H NMR (CDCl ₃ 400 MHz): δ 7.31 (t, 1H), 7.15 (d, 1H), 7.08 (s, 1H), 7.01 (d, 1H), 6.49 (t, 1H), 5.71-5.65 ( m, 1H), 5.19-5.15 (m, 2H), 4.48-4.44 (m, 1H), 3.66 (s, 1H), 2.59-2.54 (m, 1H), 2.46-2.40 (m, 1H), 1.18 ( s, 9H).

Step 3: Preparation of ( S ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)-3-oxopropyl)-2-methylpropane-2-sulfinamide

Potassium dioxido(dioxo)osmium hydrate (276 mg) was dissolved in ( S ) -N -(( S )-1-(3-(dioxane) in a mixture of dioxane (10 mL) and H ₂ O (3 mL). Fluoromethoxy)phenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (2.5 g), 2,6-lutidine (1.69 g) and sodium periodate (5.05 g) was added to the stirred solution of The reaction mixture was stirred at 20 °C for 1 h, then diluted with DCM (100 mL) and water (20 mL). The aqueous layer was extracted with DCM (25 mL×2). The combined organic extracts were dried over Na ₂ SO ₄ . The crude reaction mixture was used directly in the next step.

Step 4: Preparation of ( S ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)-3,3-difluoropropyl)-2-methylpropane-2-sulfinamide

( S ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)-3-oxopropyl)-2-methylpropane-2-sulfinamide (2 g) in DCM (200 mL) Diethylaminosulfur trifluoride (DAST) (3.03 g) at -78°C was added dropwise to a solution of The reaction mixture was brought to 20° C. and stirred for 2 h. The solution was poured into saturated aqueous NaHCO ₃ (50 mL) and the organic phase was separated. The solution was dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 5/1 to 1/1) to ( S ) -N -(( S )-1-(3-(difluoromethoxy)phenyl )-3,3-difluoropropyl)-2-methylpropane-2-sulfinamide (500 mg) was obtained.

Step 5: Preparation of (1S)-1-[3-(difluoromethoxy)phenyl]-3,3-difluoro-propan-1-amine hydrochloride

( S ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)-3,3-difluoropropyl)-2-methylpropane-2-sulfinamide in MeOH (15 mL) To a solution of (380 mg) was added HCl/MeOH (25 mL, 4 M) at 0° C. and the reaction stirred for 0.5 h and brought to 25° C. The reaction mixture was concentrated to give (1S)-1-[3-(difluoromethoxy)phenyl]-3,3-difluoro-propan-1-amine hydrochloride (300 mg, crude, HCl salt) . It was used directly without further purification.

IIj: ( S )-1-(3-(difluoromethoxy)phenyl)ethan-1-amine hydrochloride

Step 1: Preparation of (( S , E ) -N- (3-(difluoro-methoxy)benzylidene)-2-methylpropane-2-sulfinamide

To a mixture of 3-(difluoromethoxy)benzaldehyde (2 g) and ( R )-2-methylpropane-2-sulfinamide (1.7 g) in DCE (60 mL) under N ₂ CuSO ₄ at 55° C. (9.3 g) was added. The reaction mixture was stirred at 55° C. for 12 h, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column (petroleum ether/ethyl acetate = 20:1-10:1) to (( S , E ) -N- (3-(difluoro-methoxy)benzyl Yiden)-2-methylpropane-2-sulfinamide (4.5 g) was produced.

Step 2: Preparation of ( S ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide

In a solution of (( S , E ) -N- (3-(difluoro-methoxy)benzylidene)-2-methylpropane-2-sulfinamide (2 g) in DCM (30 mL) at 0 °C Mo(methyl)magnesium (3 M in Et ₂ O, 4.8 mL) was added dropwise. The resulting mixture was stirred at 0° C. for 1 h and at 20° C. for 16 h. The reaction was stirred with aqueous saturated NH ₄ Cl (10 mL). ), and the aqueous phase was extracted with ethyl acetate (30 mL×3).The combined organic extracts were washed with brine (40 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated, Purification by chromatography on silica gel (petroleum ether/ethyl acetate = 5:1 to 1:1) ( S ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)ethyl) -2-methylpropane-2-sulfinamide (960 mg) was obtained.

Step 3: Preparation of ( S )-1-(3-(difluoromethoxy)phenyl)ethan-1-amine hydrochloride

HCl in a solution of ( S ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (0.8 g) in MeOH (4 mL) /MeOH (4 M, 2 mL) was added. The resulting mixture was stirred at 25° C. for 3 hours and concentrated to give ( S )-1-(3-(difluoromethoxy)phenyl)ethan-1-amine hydrochloride (1.6 g, crude).

IIk: ( R )-2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine hydrochloride

Step 1: Preparation of ethyl ( R , E )-2-(( tert -butylsulfinyl)imino)acetate

To a solution of ethyl 2-oxoacetate (7.5 g) and (R)-2-methylpropane-2-sulfinamide (4.90 g) in DCM (150 mL) under N ₂ was added CuSO ₄ (12.9 g), the reaction The mixture was stirred at 25° C. for 24 h. The solid was filtered, washed with ethyl acetate (50 mL), and the organic layer was concentrated. The residue was purified by chromatography (SiO ₂ , hexane/ethyl acetate, 5/1) to give ethyl ( R , E )-2-(( tert -butylsulfinyl)imino)acetate (5 g).

Step 2: Preparation of ethyl ( R )-2-((( S ) -tert -butylsulfinyl)amino)-2-(3-(trifluoromethoxy)phenyl)acetate

Ethyl ( R , E )-2-(( tert -butylsulfinyl)imino)acetate (5 g) and [3-(trifluoromethoxy)phenyl]boronic acid (6.02 g) in dioxane (80 mL) Bis(acetonitrile)(1,5-cyclooctadiene)rhodium(I)tetrafluoroborate (CAS: 32679-02-0) (1.85 g) was added to a solution of stirred for a while. The solution was filtered and the organic phase was concentrated. The residue was purified by chromatography (SiO ₂ , petroleum ether: EtOAc = 6:1) to ethyl ( R )-2-((( S ) -tert -butylsulfinyl)amino)-2-(3-( Trifluoromethoxy)phenyl)acetate (5.1 g) was obtained.

Step 3: Preparation of ethyl ( R )-2-amino-2-(3-(trifluoromethoxy)phenyl)acetate

To a solution of ethyl ( R )-2-((( S ) -tert -butylsulfinyl)amino)-2-(3-(trifluoromethoxy)phenyl)acetate (4.6 g) in MeOH (30 mL) was 0 HCl/MeOH (4 M, 25.04 mL) at °C was added. The reaction mixture was stirred at 25° C. for 1 hour and concentrated to give ethyl ( R )-2-amino-2-(3-(trifluoromethoxy)phenyl)acetate as the hydrochloride salt (3.3 g).

Step 4: Preparation of ethyl ( R )-2-(( tert -butoxycarbonyl)amino)-2-(3-(trifluoromethoxy)phenyl)acetate

To a mixture of ethyl ( R )-2-amino-2-(3-(trifluoromethoxy)phenyl)acetate hydrochloride (3.3 g) in THF (80 mL) with Boc ₂ O (4.81 g) and NaHCO ₃ (925 mg) was added and the reaction was stirred at 25° C. for 16 h. The reaction mixture was concentrated, diluted with EtOAc (20 mL), washed with water (20 mL), then concentrated. The residue was purified by chromatography (SiO ₂ ; petroleum ether: EtOAc = 10:1) to ethyl ( R )-2-(( tert -butoxycarbonyl)amino)-2-(3-(trifluoromethyl). Toxy)phenyl)acetate (3.8 g) was obtained.

Step 5: Preparation of tert -butyl ( R )-(2-hydroxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate

To a suspension of LiAlH ₄ (2.1 g) in THF (200 mL) under ice cooling ethyl ( R )-2-(( tert -butoxycarbonyl)amino)-2-(3-(tri Fluoromethoxy)phenyl)acetate (5 g) was added and the mixture was stirred at 0° C. to 25° C. for 2 h. Anhydrous magnesium sulfate was added, then water (5 mL) and ethyl acetate (100 mL) were successively added, and the insoluble material was filtered off using Celite. The filtrate was concentrated. The crude product was purified by chromatography (SiO ₂ , petroleum ether: EtOAc = 5:1) to tert -butyl ( R )-(2-hydroxy-1-(3-(trifluoromethoxy)phenyl)ethyl ) to obtain carbamate (3.37 g).

Step 6: Preparation of tert -butyl ( R )-(2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate

To a solution of tert -butyl ( R )-(2-hydroxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate (1 g) in hexanes (15 mL) diethyl sulfate (960 mg) , tetrabutyl ammonium chloride (TBAC) (87 mg) and a solution of NaOH (324 mg) in H ₂ O (1.5 mL) were added. The resulting mixture was stirred at 25° C. for 20 h. The reaction mixture was diluted with EtOAc (200 mL), washed with water (100 mL) and brine (100 mL), dried over Na ₂ SO ₄ and concentrated. The crude was purified by chromatography (SiO2, 10% ethyl acetate in petroleum ether) to tert -butyl ( R )-(2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate (5.9 g).

Step 7: Preparation of ( R )-2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine hydrochloride

To a solution of tert -butyl ( R )-(2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate (5.9 g) in MeOH (100 mL) at 25° C. in HCl/MeOH (4 M, 63.33 mL) was added and the mixture was stirred at 25° C. for 16 h. The solution was concentrated to give ( R )-2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine hydrochloride (4.5 g).

II: ( S )-1-(3-(trifluoromethoxy)phenyl)propan-1-amine hydrochloride

Step 1: Preparation of ( S , E )-2-methyl- N- (3-(trifluoromethoxy)benzylidene)propane-2-sulfinamide

A mixture of 3-(trifluoromethoxy)benzaldehyde (10.0 g), ( R )-2-methylpropane-2-sulfinamide (7.7 g) and CuSO ₄ (12.6 g) in DCE (200 mL) at 55° C. stirred for 16 hours. The mixture was filtered and the filter cake was washed with DCM (200 mL). The filtrate was concentrated. The residue was purified by chromatography (SiO ₂ , 0% to 10% ethylacetate/petroleum ether gradient) to ( S , E )-2-methyl- N- (3-(trifluoromethoxy)benzylidene)propane -2-sulfinamide (12.6 g) was produced.

Step 2: Preparation of (S)-2-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)propyl)propane-2-sulfinamide

To a solution of ( S , E )-2-methyl- N- (3-(trifluoromethoxy)benzylidene)propane-2-sulfinamide (2.0 g) in DCM (40 mL) at 0 °C with EtMgBr(Et) 3 M in ₂ O, 9.1 mL) was added dropwise. The resulting mixture was stirred at 0° C. for 1 hour and at 20° C. for 3 hours. The mixture was cooled to 0° C. and saturated aqueous NH ₄ Cl (100 mL) was added. The mixture was extracted with DCM (100 mL×2), the phases were separated and the organic layer washed with brine (200 mL), dried over Na ₂ SO ₄ and concentrated. The residue was purified by chromatography (SiO ₂ , 0% to 50% ethyl acetate/petroleum ether gradient) to give the product (1.4 g).

Step 3: Preparation of ( S )-1-(3-(trifluoromethoxy)phenyl)propan-1-amine hydrochloride

HCl in a solution of ( S )-2-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)propyl)propane-2-sulfinamide (1.4 g) in MeOH (40 mL) /MeOH (4 M, 20 mL) was added. The resulting mixture was stirred at 30° C. for 12 hours, then concentrated to give crude ( S )-1-(3-(trifluoromethoxy)phenyl)propan-1-amine hydrochloride (1 g), This was used without further purification.

IIm: ( S )-3-Amino-3-(3-(trifluoromethoxy)phenyl)propanenitrile hydrochloride

Step 1: Preparation of tert -butyl ( R )-(2-hydroxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate

This intermediate was prepared as described in Intermediate IIk, Steps 1-5 .

Step 2: Preparation of ( R )-2-(( tert -butoxycarbonyl)amino)-2-(3-(trifluoromethoxy)phenyl)ethyl methanesulfonate

To a solution of tert -butyl ( R )-(2-hydroxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate (2 g) in DCM (20 mL) Et ₃ N (756 mg) was added, and then methanesulfonyl chloride (1.75 g) was added at 0 °C. The mixture was stirred at 20° C. for 16 h. The reaction mixture was washed with saturated aqueous NH ₄ Cl solution (15 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated ( R )-2-(( tert -butoxycarbonyl)amino)-2- (3-(trifluoromethoxy)phenyl)ethyl methanesulfonate (2.50 g, crude) was obtained, which was used in the next step without purification.

Step 3: Preparation of (S)-3-amino-3-(3-(trifluoromethoxy)phenyl)propanenitrile hydrochloride

To a solution of ( R )-2-(( tert -butoxycarbonyl)amino)-2-(3-(trifluoromethoxy)phenyl)ethyl methanesulfonate (420 mg) in DMSO (5 mL) at 20 °C KCN (225 mg) from was added. The mixture was stirred at 50° C. for 16 h. The reaction mixture was diluted with 10% Na ₂ CO ₃ solution (40 mL) and extracted with EtOAc (30 mL×3). The combined organic extracts were washed with water (50 mL) and brine (50 mL), then dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 4/1) to tert -butyl (S)-(2-cyano-1-(3-(trifluoromethoxy) )phenyl)ethyl)carbamate (665 mg) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.46 (t, 1H), 7.33 (d, 1H), 7.24 (m, 2H), 7.04 (d, 1H), 5.31-5.38 (m, 1H), 3.73 -3.71 (m, 1H), 3.11-3.05 (m, 1H), 2.84-2.92 (m, 2H), 2.49-2.43 (m, 1H), 2.28-2.37 (m, 1H), 0.93 (s, 9H) .

To a solution of tert -butyl (S)-(2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate (400 mg) in MeOH (8 mL) at 0° C. in HCl/MeOH (4 M, 4.00 mL) was added. The mixture was stirred at 25° C. for 16 h. Then, the reaction mixture was concentrated to give ( S )-3-amino-3-(3-(trifluoromethoxy)phenyl)propanenitrile hydrochloride (280 mg, crude).

IIn: ( S )-4-amino-4-(3-(trifluoromethoxy)phenyl)butanenitrile hydrochloride

Step 1: Preparation of ( R , E )-2-methyl- N- (3-(trifluoro-methoxy)benzylidene)propane-2-sulfinamide

To a solution of 3-(trifluoromethoxy)benzaldehyde (30 g) and ( R )-2-methylpropane-2-sulfinamide (23.0 g) in DCE (600 mL) was added CuSO ₄ (37.8 g) . The mixture was stirred at 55° C. for 24 h and filtered. The filter cake was washed with DCM (300 mL). The filtrates were combined and concentrated, and the residue was purified by chromatography (SiO ₂ , petroleum ether/ethyl acetate = 0/1 to 5:1) ( R , E )-2-methyl- N- (3-( Trifluoro-methoxy)benzylidene)propane-2-sulfinamide (41.8 g) was obtained.

Step 2: Preparation of ethyl ( S )-3-((( R ) -tert -butylsulfinyl)amino)-3-(3-(trifluoromethoxy)phenyl)propanoate

A solution of ( R , E )-2-methyl- N- (3-(trifluoro-methoxy)benzylidene)propane-2-sulfinamide (5 g) in THF (60 mL) at 0° C. in THF To a suspension of activated Zn (11.15 g), CuCl (2.5 g) and ethyl 2-bromoacetate (7.1 g) in (60 mL). The reaction mixture was stirred at 50° C. for 2 h and filtered. The filter cake was washed with DCM (400 mL) and the combined organic filtrates were concentrated. The residue was purified by chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 5/1) to ethyl ( S )-3-((( R ) -tert -butylsulfinyl)amino)-3 -(3-(trifluoromethoxy)phenyl)propanoate (7 g, crude) was obtained.

¹ H NMR (CDCl ₃ 400 MHz): δ 7.36 (t, 2H), 7.20 (s, 1H), 7.14 (d, 1H), 5.78 (d, 1H), 5.14-5.10 (m, 1H), 4.14-4.10 (m, 2H), 3.05-2.89 (m, 2H), 1.31 (s, 9H), 1.18 (t, 3H).

Step 3: Preparation of ( R ) -N -(( S )-3-hydroxy-1-(3-(trifluoromethoxy)phenyl)propyl)-2-methylpropane-2-sulfinamide

A solution of ethyl ( S )-3-((( R ) -tert -butylsulfinyl)amino)-3-(3-(trifluoromethoxy)phenyl)propanoate (7 g) in THF (70 mL) was added LiAlH ₄ (696 mg) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h, then quenched by sequential addition of H ₂ O (0.7 mL), 10% NaOH (0.7 mL) solution and H ₂ O (2.1 mL) at 0 °C. The mixture was filtered. Concentrate the residue to obtain crude ( R ) -N -(( S )-3-hydroxy-1-(3-(trifluoromethoxy)phenyl)propyl)-2-methylpropane-2-sulfinamide (4.2 g) was obtained.

Step 4: Preparation of ( S )-3-amino-3-(3-(trifluoromethoxy)phenyl)propan-1-ol hydrochloride

Crude ( R ) -N -(( S )-3-hydroxy-1-(3-(trifluoromethoxy)phenyl)propyl)-2-methylpropane-2-sulfinamide from the previous reaction step ( 4 g) was dissolved in MeOH (40 mL) and HCl/MeOH (4 M, 23.6 mL) was added. The reaction mixture was stirred at 20 °C for 16 h and concentrated to give ( S )-3-amino-3-(3-(trifluoromethoxy)phenyl)propan-1-ol hydrochloride (3.2 g, crude) .

Step 5: Preparation of tert -butyl ( S )-(3-hydroxy-1-(3-(trifluoromethoxy)phenyl)propyl)carbamate

Crude ethyl ( S )-3-((( R ) -tert -butylsulfinyl)amino)-3-(3-(trifluoromethoxy)phenyl)propanoate from the previous reaction step (3.2 g) was dissolved in THF (35 mL) and Boc ₂ O (10.28 g) and NaHCO 3 (2 g) were added. The reaction mixture was stirred at 20° C. for 16 h. The mixture was concentrated, the residue was diluted with water (70 mL), extracted with DCM (100 mL×3) and the combined organic extracts dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 2/1) to tert -butyl ( S )-(3-hydroxy-1-(3-(trifluoromethoxy) )phenyl)propyl)carbamate (3.2 g) was obtained.

Step 6: Preparation of ( S )-3-(( tert -butoxycarbonyl)amino)-3-(3-(trifluoromethoxy)phenyl)propyl methanesulfonate

To a solution of tert -butyl ( S )-(3-hydroxy-1-(3-(trifluoromethoxy)phenyl)propyl)carbamate (1 g) in DCM (30 mL) Et ₃ N at 0 °C (905 mg) and methanesulfonyl chloride (683 mg) were added. The reaction mixture was stirred at 20° C. for 16 h, then washed with ice water (15 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated (( S )-3-(( tert -butoxycarbonyl). )amino)-3-(3-(trifluoromethoxy)phenyl)propyl methanesulfonate (1.2 g) was obtained.

Step 7: Preparation of tert -butyl ( S )-(3-cyano-1-(3-(trifluoromethoxy)phenyl)propyl)carbamate

(( S )-3-(( tert -butoxycarbonyl)amino)-3-(3-(trifluoromethoxy)phenyl)propyl methanesulfonate obtained in the previous step was dissolved in DMSO (35 mL) and , was added KCN (661 mg) at 20° C. The reaction mixture was stirred at 50° C. for 16 h, then diluted with 10% Na ₂ CO ₃ solution (40 mL) and extracted with EtOAc (70 mL×3). The combined organic extracts were washed with water (50 mL) and brine (50 mL), then dried over Na ₂ SO ₄ , filtered and concentrated The residue was chromatographed (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 3/1) to give tert -butyl ( S )-(3-cyano-1-(3-(trifluoromethoxy)phenyl)propyl)carbamate (990 mg).

Step 8: Preparation of ( S )-4-amino-4-(3-(trifluoromethoxy)phenyl)butanenitrile hydrochloride

To a solution of tert -butyl ( S )-(3-cyano-1-(3-(trifluoromethoxy)phenyl)propyl)carbamate (900 mg) in MeOH (14 mL) HCl/MeOH (4 M, 6.53 mL) was added. The mixture was stirred at 20 °C for 16 h and concentrated to give ( S )-4-amino-4-(3-(trifluoromethoxy)phenyl)butanenitrile hydrochloride (850 mg).

IIo: ( S )-3,3-difluoro-1-(3-(trifluoromethoxy)phenyl)propan-1-amine hydrochloride

Prepared as described for IIi using 3-(trifluoromethoxy)benzaldehyde as starting material.

IIp: ( R )-2-Methoxy-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine hydrochloride

Step 1: Preparation of ethyl ( R )-2-(( tert -butoxycarbonyl)amino)-2-(3-(trifluoromethoxy)phenyl)acetate

This intermediate was prepared as described in IIk , steps 1-4.

Step 2: Preparation of tert -butyl ( R )-(2-hydroxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate

To a solution of ethyl ( R )-2-(( tert -butoxycarbonyl)amino)-2-(3-(trifluoromethoxy)phenyl)acetate (10 g) in EtOH (90 mL) at 0° C. (4.17 g) was added. The mixture was removed from the cold bath and stirred for 2 h. The reaction was quenched with water (20 mL) and concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 3/1) to give the product (13.6 g).

1H NMR (CDCl ₃ 400MHz): δ 7.39 (t, 1H), 7.26 (d, 1H), 7.17-7.15 (m, 2H), 5.34 (s, 1H), 4.80 (s, 1H), 3.93-3.84 ( m, 2H), 2.06 (s, 1H), 1.45 (s, 9H).

Step 3: Preparation of tert -butyl ( R )-(2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate

To a solution of tert -butyl ( R )-(2-hydroxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate (1 g) and MeI (4 g) in THF (70 mL) 0 NaH at °C (149 mg, 60% in mineral oil) was added. The mixture was stirred at 0° C. for 1 h and at 25° C. for 16 h. Water (1 mL) was added to quench the reaction. THF was removed and EtOAc (200 mL) was added to the residue. The solution was washed with water (50 mL×3) and concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 0/1 to 5/1) to tert -butyl ( R )-(2-methoxy-1-(3-(trifluoromethyl) Toxyl)phenyl)ethyl)carbamate (3.2 g) was obtained.

¹ H NMR (CDCl ₃ 400 MHz): δ 7.36 (t, 1H), 7.25 (m, 1H), 7.19 (s, 1H), 7.12 (d, 1H), 5.34 (s, 1H), 4.83 (s, 1H) ), 3.63-3.56 (m, 2H), 3.35 (s, 3H), 1.43 (s, 9H).

Step 4: Preparation of ( R )-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine hydrochloride

To a solution of tert -butyl ( R )-(2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate (2.7 g) in MeOH (40 mL) at 25° C. in HCl/MeOH (4 M, 40 mL) was added. The mixture was stirred at 25° C. for 16 h. The mixture was concentrated to give the desired product (1.9 g, crude).

IIIa: ( S )-3-hydroxy-4,4-dimethylpentanoic acid

It was prepared as described in Wang Z. et al: Tetrahedron: Asymmetry 10 (1999) 225-228.

IIIb: 2-(3,3-difluoro-1-hydroxycyclobutyl)acetic acid

Step 1: Preparation of ethyl 2-(3,3-difluoro-1-hydroxy-cyclobutyl)acetate

To a solution of 3,3-difluorocyclobutanone (0.2 g), Zn (198 mg) and I ₂ (10 mg) in THF (13 mL) under N ₂ was ethyl 2-bromoacetate (378 mg) was added dropwise. The mixture was stirred at 55° C. for 6 hours. H ₂ SO ₄ (10%, 10 mL) was carefully added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate (20 mL×3). The organic extracts were washed with NaHCO ₃ (sat. aq., 10 mL), dried over Na ₂ SO ₄ and concentrated. The crude product (0.26 g) was used directly without further purification.

Step 2: Preparation of 2-(3,3-difluoro-1-hydroxy-cyclobutyl)acetic acid

To a solution of ethyl 2-(3,3-difluoro-1-hydroxy-cyclobutyl)acetate (0.26 g) in MeOH (10 mL) and H ₂ O (2 mL) was added NaOH (107 mg) at 0° C. was added in The mixture was stirred at 20° C. for 8 hours. The reaction solution was cooled to 0° C. and 1 N HCl was added to the solution until the pH reached 1-2. The residue was diluted with brine (10 mL) and extracted with methyl- tert -butyl ether (30 mL×5). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated. The crude product (0.24 g) was used without further purification.

IIIc: 3-(1-fluorocyclopropyl)-3-hydroxybutanoic acid

Step 1: Preparation of ethyl 3-(1-fluorocyclopropyl)-3-hydroxy-butanoate

A solution of 1-(1-fluorocyclopropyl)ethanone (0.5 g), Zn (512 mg) and I ₂ (62 mg) in THF (30 mL) was stirred at 20° C. until colorless, ethyl 2-Bromoacetate (981 mg) was added dropwise. The resulting mixture was stirred at 20° C. for 0.5 h and at 65° C. for 4.5 h. The reaction was washed with 10% aq. H ₂ SO ₄ (20 mL) and extracted with EtOAc (50 mL×2). The organic extracts were washed with brine (100 mL), dried over Na ₂ SO ₄ and concentrated to give ethyl 3-(1-fluorocyclopropyl)-3-hydroxy-butanoate (0.83 g, crude). .

Step 2: Preparation of 3-(1-fluorocyclopropyl)-3-hydroxy-butanoic acid

To a solution of ethyl 3-(1-fluorocyclopropyl)-3-hydroxy-butanoate (0.83 g) in EtOH (10 mL) was added a solution of NaOH (350 mg) in H ₂ O (3 mL) did The reaction mixture was stirred at 20° C. for 2 h, then extracted with EtOAc (50 mL×2). The aqueous layer was acidified to pH = 3 with 10% HCl and extracted with EtOAc (50 mL×2). The combined organic extracts were washed with brine (100 mL), dried over Na ₂ SO ₄ and concentrated to give 3-(1-fluorocyclopropyl)-3-hydroxy-butanoic acid (0.57 g, crude).

IIId : 3- cyclopropyl -3- hydroxybutanoic acid

Step 1: Preparation of methyl 3-cyclopropyl-3-hydroxybutanoate

To Zn (12.4 g) in THF (150 mL) was added TMSCl (1.3 g) and the resulting mixture was stirred at 20° C. for 15 min, then heated to 70° C. Heating was stopped and methyl 2-bromoacetate (21.8 g) was added dropwise at a rate at which the solvent slowly boiled. The resulting mixture was stirred at 70° C. for 1 h and at 20° C. for 1 h, after which a solution of 1-cyclopropylethanone (10 g) in THF (50 mL) was added. The reaction was stirred at 20 °C for 16 h. The mixture was stirred in ice with NH ₃ ^. Poured into H ₂ O (100 mL, 28%) and extracted with ethyl acetate (150 mL×2). The organic extracts were washed with water (150 mL) and brine (150 mL), dried over Na ₂ SO ₄ and concentrated to give the desired product (8.9 g, crude).

Step 2: Preparation of 3-cyclopropyl-3-hydroxybutanoic acid

Crude methyl 3-cyclopropyl-3-hydroxybutanoate (8.9 g) and LiOH in THF (100 mL) and H ₂ O (50 mL) ^. A mixture of H ₂ O (11.8 g) was stirred at 20° C. for 16 h. H ₂ O (50 ml) was added and extracted with ethyl acetate (100 mL×2). The organic extract was discarded. The pH of the aqueous layer was adjusted to about 5 with 2 N HCl, extracted with ethyl acetate (100 mL×3) and the combined organic fractions washed with brine (100 mL×10), dried over Na ₂ SO ₄ , filtered and concentrated. to give the desired product (5.1 g) in 30% overall yield.

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.67-2.51 (m, 2H), 1.25 (s, 3H), 0.90-1.00 (m, 1H), 0.33-0.50 (m, 4H).

IIIe: 5,5,5-trifluoro-3-hydroxy-3-methylpentanoic acid

Step 1: Preparation of ethyl 5,5,5-trifluoro-3-hydroxy-3-methylpentanoate

To a mixture of Zn (6.9 g) and I ₂ (89 mg) in THF (80 mL) at 15° C. 4,4,4-trifluorobutan-2-one (4.4 g) and ethyl 2-bromoacetate (6.4 g) was added. The mixture was stirred at 60° C. for 6 hours. The reaction mixture was cooled to 0° C. and quenched with H ₂ SO ₄ (100 mL, 10% aq). The mixture was extracted with ethyl acetate (15 mL×3). The combined organic extracts were washed with brine (15 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The product was obtained (11.00 g, crude) and used directly without further purification.

Step 2: Preparation of 5,5,5-trifluoro-3-hydroxy-3-methylpentanoic acid

A mixture of ethyl 5,5,5-trifluoro-3-hydroxy-3-methyl-pentanoate (11 g, crude) and NaOH (4.1 g) in H ₂ O (150 mL) at 15° C. Stirred for 16 hours. The pH was adjusted to about 2 with saturated KHSO ₄ at 0° C. and the mixture was extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with brine (300 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give the product (10 g, crude).

The following were prepared by the same methodology as described for IIIe using the relevant starting materials:

IIIf: 3-hydroxy-3,4-dimethylpentanoic acid

¹ H NMR (CDCl ₃ 400 MHz): δ 2.65-2.46 (m, 2H), 2.09 (s, 1H), 1.85-1.76 (m, 1H), 1.20 (s, 3H), 0.93 (dd, 6H).

IIIg: 3-Hydroxy-3,5-dimethyl-hexanoic acid

¹ H NMR (CDCl ₃ 400 MHz): δ 2.64-2.50 (m, 2H), 1.85-1.79 (m, 1H), 1.49 (d, 2H), 1.32 (s, 3H), 1.03-0.97 (m, 6H) .

IIIh: 3-(3,3-Dimethylcyclobutyl)-3-hydroxy-propanoic acid

Step 1: Preparation of ethyl 3-(3,3-dimethylcyclobutyl)-3-hydroxy-propanoate

To a solution of ethyl 3-(3,3-dimethylcyclobutyl)-3-oxo-propanoate ( IVd ) (1 g) in MeOH (8 mL) was added NaBH ₄ (95 mg). The mixture was stirred at 0° C. for 10 min, quenched by addition of H ₂ O (1 mL), concentrated, then diluted with EtOAc (30 mL), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 4/1) to ethyl 3-(3,3-dimethylcyclobutyl)-3-hydroxy-propanoate (907) mg) was obtained.

¹ H NMR (DMSO-d6 400 MHz): δ 4.70 (d, 1H), 4.06-4.00 (m, 2H), 3.71-3.68 (m, 1H), 2.26-2.23 (m, 1H), 2.15-2.12 (m) , 2H), 1.63-1.59 (m, 3H), 1.52-1.49 (m, 1H), 1.17 (t, 3H), 1.09 (s, 3H), 0.99 (s, 3H).

Step 2: Preparation of 3-(3,3-dimethylcyclobutyl)-3-hydroxy-propanoic acid

To a solution of ethyl 3-(3,3-dimethylcyclobutyl)-3-hydroxy-propanoate (900 mg) in MeOH (10 mL) was added a solution of NaOH (377 mg) in H ₂ O (5 mL). added. The mixture was stirred at 25° C. for 4 h. The reaction mixture was added to 10% HCl solution to adjust pH = 3-4, then diluted with H ₂ O (30 mL), extracted with EtOAc (30 mL×2), and the combined organic layers were combined with Na ₂ SO ₄ It was dried over, filtered and concentrated to give 3-(3,3-dimethylcyclobutyl)-3-hydroxy-propanoic acid (760 mg).

¹ H NMR (DMSO-d6 400 MHz): δ 11.96-11.95 (m, 1H), 4.65-4.61 (m, 1H), 3.71-3.66 (m, 1H), 2.19-2.05 (m, 3H), 1.63 1.51 (m, 4H), 1.09 (s, 3H), 1.00 (s, 3H).

The following were prepared by the same methodology as described for IIIh using the relevant starting materials:

IIIi: 3-cyclopentyl-3-hydroxy-propanoic acid

¹ H NMR (DMSO-d6 400 MHz): δ 11.96 (s, 1H), 4.63 (s, 1H), 3.66 (s, 1H), 2.36-2.32 (m, 2H), 1.83-1.75 (m, 1H), 1.62-1.35 (m, 8H).

IVa: ethyl 3-[1-(difluoromethyl)cyclopropyl]-3-oxo-propanoate

Step 1: Preparation of ethyl 3-[1-(difluoromethyl)cyclopropyl]-3-oxo-propanoate

Et ₃ N (2.34 g) and MgCl ₂ (1.8 g) were added to a suspension of (3-ethoxy-3-oxo-propanoyl)oxy potassium salt (2.6 g) in MeCN (30 mL), 20° C. was stirred for 2 hours. A pre-stirred mixture of carbonyl-diimidazole (CDI) (1.4 g) and 1-(difluoromethyl)cyclopropane carboxylic acid (1 g) in MeCN (20 mL) was added at 0° C. and at 20° C. Stirred for 14 hours. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with ethyl acetate (80 mL×2). The combined organic extracts were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography (SiO ₂ , eluent from 0% to 10% ethyl acetate/petroleum ether gradient) to give the product (0.98 g).

The following were prepared by the same methodology as described for IVa using the relevant starting materials:

IVb : ethyl 3-oxo-3-[1-(trifluoromethyl)cyclopropyl]propanoate

IVc: 3-(3,3-difluorocyclobutyl)-3-oxopropanoate

IVd: ethyl 3-(3,3-dimethylcyclobutyl)-3-oxo-propanoate

¹ H NMR (CDCl ₃ 400 MHz): δ 4.22-4.16 (m, 1H), 3.39 (s, 2H), 3.34-3.25 (m, 1H), 2.08-1.90 (m, 4H), 1.29 (t, 3H) , 1.27 (s, 3H), 1.06 (s, 3H).

IVe: ethyl 3-cyclopentyl-3-oxo-propanoate

¹ H NMR (CDCl ₃ 400 MHz): δ 4.24-4.18 (m, 2H), 3.49 (s, 2H), 3.03-2.95 (m, 1H), 1.84-1.60 (m, 8H), 1.28 (t, 3H) .

IVf: ethyl 3-(1-ethylcyclopropyl)-3-oxo-propanoate

¹ H NMR (CDCl ₃ 400 MHz): δ 4.22-4.16 (m, 2H), 3.33 (s, 2H), 1.64-1.60 (m, 2H), 1.26-1.20 (m, 6H), 0.94 (t, 3H) .

Va: ( R )- N -(2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-4,4-dimethyl-3-oxopentanamide

Step 1: Preparation of ( R )-N-(2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-4,4- dimethyl -3-oxopentanamide

(R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethan-1-amine hydrochloride ( IIa ) (0.6 g) in toluene (10 mL), methyl 4, A solution of 4-dimethyl-3-oxo-pentanoate (750 mg), TEA (2.40 g) and DMAP (58 mg) was stirred at 90° C. for 16 h. The mixture was diluted with EtOAc (50 mL), washed with water (30 mL) and brine (50 mL), dried over Na ₂ SO ₄ and concentrated. The crude was purified by chromatography (SiO ₂ , 30% EA in petroleum ether ) to ( R )-N-(2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl )-4,4-dimethyl-3-oxopentanamide (0.28 g).

The following intermediates were prepared by a methodology analogous to Va using the relevant intermediates:

Vb: ( R )- N -(2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethyl-3-oxopentanamide

IIk and 4,4-dimethyl-3-oxo-pentanoic acid.

Vc: ( R )- N -(2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-oxo-3-(1-(trifluoro-methyl)cyclopropyl)propanamide

prepared from IIa and IVb .

Vd: ( R )- N -(2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-oxo-3-(1-trifluoromethyl)cyclopropyl)propanamide

prepared from IVb and IIb .

Ve: ( R )-3-(3,3-difluorocyclobutyl)- N -(2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-oxopropanamide

prepared from IVc and IIa .

Vf: ( R )-3-(3,3-difluorocyclobutyl)- N -(2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-oxopropanamide

prepared from IVc and IIb .

Vg: ( S )-3-(3,3-difluorocyclobutyl)- N -(1-(3-(difluoromethoxy)phenyl)butyl)-3-oxopropanamide

prepared from IVc and IIg .

Vh: ( R )- N -(2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-oxopropanamide

IVf and IIa .

Example:

Example 1a: N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

and Example 1b: N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

Step 1: Preparation of N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

( R )-N-(2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-4,4- dimethyl -3-oxopentanamide in MeOH (10 mL) ( To a solution of Va ) (0.28 g) was added NaBH ₄ (56 mg) at 0°C. The resulting mixture was stirred at 0° C. for 1 h. The mixture was concentrated and the residue was redissolved in EtOAc (50 mL), washed with water (50 mL) and brine (50 mL), dried over Na ₂ SO ₄ and concentrated.

Step 2: ( R ) -N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentane Amide and ( S)-N-((R) -2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide separation of

Chromatographic separation of N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide did

Example 1a :

¹ H NMR (CDCl ₃ 400 MHz): δ 7.34 (t, 1H), 7.16 (d, 1H), 7.09 (s, 1H), 7.04 (d, 1H), 6.59 (d, 1H), 6.50 (t, 1H), 6.20 (t, 1H), 5.30-5.26 (m, 1H), 4.15-4.08 (m, 2H), 3.69-3.66 (m, 1H), 2.90 (d, 1H), 2.43 (dd, 1H) , 2.28 (dd, 1H), 0.91 (s, 9H).

LC-MS : t _R = 2.49 min (LC-MS method 1), m/z =382.2 [M + H] ⁺ .

SFC : t _R = 1.94 min (SFC method 1), ee% = 95.26%.

Example 1b:

¹ H NMR (CDCl ₃ 400 MHz): δ 7.35 (t, 1H), 7.16 (d, 1H), 7.06-7.04 (m, 2H), 6.60 (d, 1H), 6.50 (t, 1H), 6.20 ( t, 1H), 5.28 (m, 1H), 4.10 (m, 2H), 3.67 (m, 1H), 3.04 (d, 1H), 2.45 (dd, 1H), 2.28 (dd, 1H), 0.91 (s) , 9H).

LC-MS : t _R = 2.50 min (LC-MS method 1), m/z = 382.2 [M + H] ⁺ .

SFC : t _R = 2.03 min (SFC method 1), ee% = 95.26%.

The following examples were prepared by a methodology analogous to that described for 1a and 1b using the relevant intermediates:

Example 2a: N -(( R )-2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

and Example 2b: N -(( R )-2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

Step 1: Preparation of N -(( R )-2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

prepared from Vb .

Step 2: ( S )-3-hydroxy-4,4-dimethyl- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide and Isolation of ( R )-3-hydroxy-4,4-dimethyl- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide

N-((R)-2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide was isolated by chromatography.

Example 2a:

¹ H NMR (DMSO-d6 300 MHz): δ 8.34 (d, 1H), 7.48-7.35 (m, 3H), 7.23 (d, 1H), 5.07 (d, 1H), 4.61 (d, 1H), 3.34 3.54 (m, 5H), 2.31-2.20 (m, 1H), 2.17-2.08 (m, 1H), 1.08 (t, 2H), 0.83 (s, 9H).

LC-MS : t _R = 1.87 min (LC-MS Method 4), m/z = 378.2 [M + H] ⁺ .

SFC : t _R = 1.71 min (SFC method 18), ee% = 96.0%.

Example 2b :

¹ H NMR (DMSO-d6 300 MHz): δ 8.39 (d, 1H), 7.46 (t, J=7.8 Hz, 5H), 7.35 (t, 2H), 7.23 (d, 3H), 5.06 (d, 1H) , 4.63 (d, 1H), 3.56-3.52 (m, 3H), 3.49-3.43 (m, 2H), 2.29-2.25 (m, 1H), 2.19-2.08 (m, 1H), 1.07 (t, , 2H) ), 0.82 (s, 9H).

LC-MS : t _R = 1.87 min (LC-MS method 4), m/z = 378.2 [M + H] ⁺ .

SFC : t _R = 1.82 min (SFC method 18), ee% = 99.1%.

Example 3a: N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl)propanamide

and

Example 3b: N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl)propanamide

Step 1: N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoro- Preparation of methyl)cyclopropyl)propanamide

prepared from Vc .

Step 2: ( R ) -N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-( trifluoro-methyl)cyclopropyl)propanamide and ( S ) -N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3- Isolation of hydroxy-3-(1-(trifluoro-methyl)cyclopropyl)propanamide

N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl ) propanamide was isolated by chiral SFC.

Example 3a:

¹ H NMR (CDCl ₃ 400 MHz): δ 7.35 (t, 1H), 7.16 (d, 1H), 7.07-7.05 (m, 2H), 6.45 (t, 1H), 6.33 (s, 1H), 6.22 (t) , 1H), 5.28-5.24 (m, 1H), 4.17-4.04 (m, 3H), 3.68 (s, 1H), 2.67 (dd, 1H), 2.55 (dd, 1H), 0.92-0.88 (m, 3H) ), 0.85-0.82 (m, 1H).

LC-MS : t _R = 2.51 min (LCMS method 1), m/z = 434.1 [M + H] ⁺ .

SFC : t _R = 1.95 min (SFC method 3), ee% = 100%.

Example 3b:

¹ H NMR (CDCl ₃ 400 MHz): δ 7.36 (t, 1H), 7.16 (d, 1H), 7.06 (m, 2H), 6.50 (t, 1H), 6.38 (d, 1H), 6.21 (t, 1H) ), 5.27-5.23 (m, 1H), 4.13-4.04 (m, 3H), 3.76 (d, 1H), 2.67-2.56 (m, 2H), 0.98-0.87 (m, 4H).

LC-MS : t _R = 2.51 min (LCMS method 1), m/z = 434.1 [M + H] ⁺ .

SFC : t _R = 1.58 min (SFC method 3), ee% = 90,0%.

Example 4a: N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl)propanamide

and

Example 4b: N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl)propanamide

Step 1: N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoro- Preparation of methyl)cyclopropyl)propanamide

prepared from Vd .

Step 2: ( R ) -N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-( trifluoromethyl)cyclopropyl)propanamide and ( S ) -N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydr Isolation of hydroxy-3-(1-(trifluoromethyl)cyclopropyl)propanamide

N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl ) propanamide was isolated by chiral SFC.

Example 4a:

¹ H NMR (CDCl ₃ 400 MHz): δ 7.41 (t, 1H), 7.27 (s, 1H), 7.18 (m, 2H), 6.41 (s, 1H), 6.23 (t, 1H), 5.30 (s, 1H) ), 4.16-4.06 (m, 3H), 3.74 (s, 1H), 2.69-2.56 (m, 2H), 1.00-0.90 (m, 4H).

LC-MS: t _R = 2.53 min (LCMS Method 2), m/z = 452.1 [M + H] ⁺ .

SFC : t _R = 1.21 min (SFC method 7), ee% = 100%.

Example 4b:

¹ H NMR (CDCl ₃ 400 MHz): δ 7.40 (t, 1H), 7.27 (s, 1H), 7.18 (m, 2H), 6.42 (s, 1H), 6.24 (t, 1H), 5.30 (s, 1H) ), 4.19-4.05 (m, 3H), 3.69 (s, 1H), 2.71-2.55 (m, 2H), 0.93-0.83 (m, 4H).

LC-MS : t _R =2.63 min (LCMS method 1), m/z = 452.1 [M + H] ⁺ .

SFC : t _R = 1.57 min (SFC method 7), ee% = 99.8%.

Example 5a: 3-(3,3-difluorocyclobutyl)- N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide

and

Example 5b: 3-(3,3-difluorocyclobutyl)- N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide

Step 1: ( R )-3-( 3,3 -difluorocyclobutyl)-N-(2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3 -Preparation of oxopropanamide

It was prepared from Ve .

Step 2: ( R )-3-(3,3-difluorocyclobutyl) -N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl) Ethyl)-3-hydroxypropanamide and ( S)-3-(3,3-difluorocyclobutyl) -N -(( R )-2-(difluoromethoxy)-1-(3-( Separation of difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide

( R )-3-(3,3-difluorocyclobutyl)-N-(2-(trifluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3- oxopropane Amide was isolated by chiral SFC

Example 5a:

¹ H NMR (CDCl ₃ 400 MHz): δ 7.37 (t, 1H), 7.17 (d, 1H), 7.09-7.07 (m, 2H), 6.51 (t, 1H), 6.32 (m, 1H), 6.13 (t) , 1H), 5.30-5.25 (m, 1H), 4.18-4.14 (m, 1H), 4.10-4.06 (m, 1H), 4.00-3.96 (m, 1H), 3.64 (d, 1H), 2.59-2.55 (m, 3H), 2.45-2.35 (m, 2H), 2.34-2.26 (m, 1H), 2.21-2.08 (m, 1H).

LC-MS : t _R =2.74 min (LCMS Method 1), m/z = 416.1 [M + H] ⁺ .

SFC : t _R = 2.49 min (SFC method 4), ee% = 97.7%.

Example 5b :

¹ H NMR (CDCl ₃ 400 MHz): δ 7.37 (t, 1H), 7.17 (d, 1H), 7.08-7.07 (m, 2H), 6.51 (t, 1H), 6.32 (m, 1H), 6.23 (t) , 1H), 5.30-5.26 (m, 1H), 4.18-4.15 (m, 1H), 4.11-4.07 (m, 1H), 4.02-3.98 (m, 1H), 2.64-2.51 (m, 3H), 2.45 -2.36 (m, 2H), 2.33-2.25 (m, 1H), 2.21-2.16 (m, 1H).

LC-MS : t _R =2.73 min (LCMS Method 1), m/z = 416.1 [M + H] ⁺ .

SFC : t _R = 2.59 min (SFC method 4), ee% = 96.1%.

Example 6a: 3-(3,3-difluorocyclobutyl)- N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide

and

Example 6b: 3-(3,3-difluorocyclobutyl)- N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide

Step 1: ( R )-3-( 3,3 -difluorocyclobutyl)-N-(2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3 -Preparation of oxopropanamide

prepared from Vf .

Step 2: ( R )-3-(3,3-difluorocyclobutyl) -N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl) Ethyl)-3-hydroxypropanamide and ( S )-3-(3,3-difluorocyclobutyl) -N -(( R )-2-(difluoromethoxy)-1-(3-( Isolation of trifluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide

( R )-3-(3,3-difluorocyclobutyl)-N-(2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3- oxopropane The amide was isolated by chiral SFC.

Example 6a:

¹ H NMR (CDCl ₃ 400 MHz): δ 7.41 (t, 1H), 7.26 (d, 1H), 7.19 (d, 2H), 6.38 (d, 1H), 6.24 (t, 1H), 5.33-5.28 (m , 1H), 4.20-4.16 (m, 1H), 4.13-4.10 (m, 1H), 4.01-4.00 (s, 1H), 3.56 (d, 2H), 2.61-2.54 (m, 3H), 2.44-2.39 (m, 2H), 2.39-2.32 (m, 1H), 2.18 (m, 1H).

LC-MS : t _R = 2.53 min (LCMS method 1), m/z = 434.0 [M + H] ⁺ .

SFC : t _R =1.62 min (SFC method 5), ee% = 92.9%.

Example 6b:

¹ H NMR (CDCl ₃ 400 MHz): δ 7.42 (t, 1H), 7.26 (d, 1H), 7.20-7.18 (m, 2H), 6.34 (d, 1H), 6.24 (t, 1H), 5.33-5.28 (m, 1H), 4.20-4.16 (m, 1H), 4.13-4.00 (m, 1H), 4.00 (m, 1H), 3.61 (s, 1H), 2.61-2.57 (m, 3H), 2.43-2.39 (m, 2H), 2.39-2.32 (m, 1H), 2.20 (m, 1H).

LC-MS : t _R = 2.54 min (LCMS method 1), m/z = 434.0 [M + H] ⁺ .

SFC : t _R = 1.71 min (SFC method 5), ee% = 97.9%.

Example 7a: 3-(3,3-difluorocyclobutyl)- N -(( S )-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide

and

Example 7b : 3-(3,3-difluorocyclobutyl) -N -(( S )-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide

Step 1: Preparation of 3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide

prepared from Vg .

Step 2: ( S )-3-(3,3-difluorocyclobutyl) -N -(( S )-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide and ( R )-3-(3,3-difluorocyclobutyl) -N -(( S )-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide.

3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide was isolated by chiral SFC .

Example 7a:

¹ H NMR (CDCl ₃ 400 MHz): δ 7.32 (t, 1H), 7.11 (d, 1H), 7.01-7.00 (m, 2H), 6.49 (t, 1H), 5.85 (d, 1H), 4.93 ( q, 1H), 3.94-3.91 (m, 1H), 3.81 (d, 1H), 2.56-2.21 (m, 7H), 1.74-1.69 (m, 2H), 1.33-1.28 (m, 2H), 0.91 ( t, 3H).

LC-MS : t _R =2.41 min (LC-MS method 1), m/z =378.0 [M + H] ⁺ .

SFC : t _R = 2.37 min (SFC method 6), ee% = 92.4%

Example 7b :

¹ H NMR (CDCl ₃ 400 MHz): δ 7.31 (t, 1H), 7.10 (d, 1H), 7.01-7.00 (m, 2H), 6.49 (t, 1H), 5.86 (d, 1H), 4.93 ( q, 1H), 3.96-3.92 (m, 1H), 3.77 (d, 1H), 2.54-2.14 (m, 7H), 1.74-1.70 (m, 2H), 1.33-1.28 (m, 2H), 0.91 ( t, 3H).

LC-MS : t _R = 2.45 min (LC-MS Method 1), m/z =378.0 [M + H] ⁺ .

SFC : t _R = 2.49 min (SFC method 6), ee% = 99.5%

Example 8a: N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropanamide

and

Example 8b : N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxy propanamide

Step 1: N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropane Preparation of amides

prepared from Vh .

Step 2: ( S ) -N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3 -Hydroxypropanamide and ( R ) -N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl ) Isolation of -3-hydroxypropanamide

Chiral N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropanamide Separated by SFC.

Example 8a :

¹ H NMR (CDCl ₃ 400 MHz): δ 7.28 (t, 1H), 7.11 (d, 1H), 7.03 (s, 1H), 6.98 (d, 1H), 6.66 (d, 1H), 6.44 (t, 1H) ), 6.14 (t, 1H), 5.24-5.19 (m, 1H), 4.10-4.02 (m, 2H), 3.47-3.44 (m, 1H), 2.57 (d, 1H), 2.50-2.41 (m, 2H) ), 1.53-1.48 (m, 2H), 1.34-1.31 (m, 1H), 0.83-0.80 (m, 3H), 0.38-0.29 (m, 4H).

LC-MS : t _R =2.38 min (LCMS method 1), m/z = 394.0 [M + H] ⁺ .

SFC : t _R = 2.38 min (SFC method 1), ee% = 99.4%

Example 8b :

¹ H NMR (CDCl ₃ 400 MHz): δ 7.29 (t, 1H), 7.11 (d, 1H), 7.01-6.99 (m, 2H), 6.67 (d, 1H), 6.44 (t, 1H), 6.15 (t) , 1H), 5.24-5.19 (m, 1H), 4.10-4.00 (m, 2H), 3.49-3.47 (d, 1H), 2.64 (d, 1H), 2.49-2.41 (m, 2H), 1.53-1.48 (m, 2H), 1.34-1.31 (m, 1H), 0.83-0.80 (m, 3H), 0.39-0.29 (m, 4H).

LC-MS : t _R =2.38 min (LCMS method 1), m/z = 394.0 [M + H] ⁺ .

SFC : t = 2.60 min (SFC method 1), ee% = 98.7%

Example 9a: N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide

and

Example 9b: N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide

Step 1: N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxy Preparation of butanamide

( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethan-1-amine hydrochloride ( IIa ) (400 mg) and 3-( In a solution of 1-fluorocyclopropyl)-3-hydroxy-butanoic acid ( IIIc ) (307 mg) N -hydroxybenzotriazole (HOBt) (213 mg), 1-ethyl-3-(3-dimethyl Aminopropyl)carbodiimide (EDCI) (363 mg) and Et ₃ N (320 mg) were added. The mixture was stirred at 25° C. for 16 h, then diluted with water (10 mL) and extracted with EtOAc (20 mL×3). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by basal preparative HPLC and N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluoro Cyclopropyl)-3-hydroxybutanamide (250 mg) was obtained.

Step 2: ( R ) -N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)- 3-hydroxybutanamide and ( S ) -N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluoro Separation of cyclopropyl)-3-hydroxybutanamide

N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide Separated by chiral SFC.

Example 9a:

¹ H NMR (CDCl ₃ 400 MHz): δ 7.38 (t, 1H), 7.20 (d, 1H), 7.10 (m, 2H), 6.52 (t, 1H), 6.39 (d, 1H), 6.25 (t, 1H) ), 5.31 (m, 1H), 4.80 (s, 1H), 4.15 (m, 2H), 2.71 (dd, 1H), 2.54 (dd, 1H), 1.36 (s, 3H), 0.85-0.55 (m, 4H).

LC-MS : t _R = 2.48 min (LCMS Method 1), m/z = 398.2 [M + H] ⁺ .

SFC : t _R = 2.46 min (SFC method 12), ee% = 100%.

Example 9b:

¹ H NMR (CDCl ³ 400 MHz): δ 7.39 (t, 1H), 7.19 (d, 1H), 7.10-7.08 (m, 2H), 6.52 (t, 1H), 6.42 (m, 1H), 6.24 (t) , 1H), 5.33-5.28 (m, 1H), 4.71 (s, 1H), 4.19-4.10 (m, 2H), 2.72 (d, 1H), 2.52 (d, 1H), 1.36 (s, 3H), 0.99-0.85 (m, 4H).

LC-MS : t _R = 2.47 min (LCMS method 1), m/z = 398.1 [M + H] ⁺ .

SFC : t _R = 2.65 min (SFC method 12), ee% = 98.8%.

The following examples were prepared by a methodology analogous to that described for Examples 9a and 9b using the relevant intermediates:

Example 10a: N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide

and

Example 10b: N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide

Step 1: N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxy Preparation of butanamide

prepared from IIb and IIIc .

Step 2: ( S ) -N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)- 3-hydroxybutanamide and ( R ) -N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluoro Separation of cyclopropyl)-3-hydroxybutanamide

N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide Separated using chiral SFC.

Example 10a :

1H NMR (CDCl3 400MHz): δ 7.48 (t, 1H), 7.35 (d, 1H), 7.27-7.25 (m, 2H), 6.64 (d, 1H), 6.31 (t, 1H), 5.40-5.38 (m) , 1H), 4.86 (s, 1H), 4.26-4.18 (m, 2H), 2.78 (d, 1H), 2.60 (d, 1H), 1.42 (s, 3H), 0.86-0.57 (m, 4H).

LC-MS: tR = 2.64 min (LCMS Method 1), m/z = 416.2 [M + H] + .

SFC: tR = 2.38 min (SFC method 2), ee% = 100%.

Example 10b :

1H NMR (CDCl3 400MHz): δ 7.42 (t, 1H), 7.29 (m, 1H), 7.20-7.19 (m, 2H), 6.44-6.06 (m, 2H), 5.35-5.31 (m, 1H), 4.67 (s, 1H), 4.20-4.12 (m, 2H), 2.73 (dd, 1H), 2.53 (dd, 1H), 1.36 (s, 3H), 0.99-0.86 (m, 4H).

LC-MS: tR = 2.659 min (LCMS Method 1), m/z = 416.2 [M + H] + .

SFC: tR = 2.561 min (SFC method 6), ee% = 95.9%.

Example 11a: 3-cyclopropyl- N- ((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide

and

Example 11b : 3-cyclopropyl- N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide

Step 1: Preparation of 3-cyclopropyl- N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide

prepared from IIb and IIId .

Step 2: ( R )-3-cyclopropyl- N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide and ( S )-3-cyclopropyl- N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide.

3-cyclopropyl- N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide was isolated by chiral SFC .

Example 11a :

¹ H NMR (CDCl ₃ 400 MHz): δ 7.38 (t, 1H), 7.26 (d, 1H), 7.17-7.15 (m, 2H), 6.72 (d, 1H), 6.21 (t, 1H), 5.35 5.31 (m, 1H), 4.17-4.09 (m, 2H), 3.36 (s, 1H), 2.52-2.42 (m, 2H), 1.18 (s, 3H), 0.90-0.88 (m, 1H), 0.43- 0.34 (m, 4H).

LC-MS : t _R =2.42 min (LCMS method 1), m/z = 420.1 [M + Na] ⁺ .

SFC : t _R = 2.17 min (SFC method 13), ee% = 100%.

Example 11b :

¹ H NMR (CDCl ₃ 400 MHz): δ 7.39 (t, 1H), 7.29-7.20 (m, 1H), 7.21-7.16 (m, 2H), 6.74 (d, 1H), 6.23 (t, 1H), 5.36-5.32 (m, 1H), 4.19-4.10 (m, 2H), 3.40 (s, 1H), 2.49 (s, 2H), 1.18 (s, 3H), 0.90-0.87 (m, 1H), 0.41- 0.27 (m, 4H).

LC-MS : t _R =2.95 min (LCMS method 1), m/z = 420.1 [M + Na] ⁺ .

SFC : t _R = 2.48 min (SFC method 13), ee% = 100%.

Example 12a : N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy -3-methylpentanamide

and

Example 12b : N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy -3-methylpentanamide

Step 1: N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy- Preparation of 3-methylpentanamide

prepared from IIa and IIIe .

Step 2: ( R ) -N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3 -hydroxy-3-methylpentanamide and ( S ) -N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5, Isolation of 5-trifluoro-3-hydroxy-3-methylpentanamide

N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methyl Pentanamide was isolated by chiral SFC.

Example 12a:

¹ H NMR (CDCl ₃ 400 MHz): δ 7.38 (t, 1H), 7.17 (d, 1H), 7.10-7.08 (m, 2H), 6.51 (t, 1H), 6.37 (d, 1H), 6.25 (t) , 1H), 5.32-5.27 (m, 1H), 4.68 (s, 1H), 4.18 (dd, 1H), 2.52 (dd, 1H), 2.61-2.52 (m, 2H), 2.47-2.41 (m, 2H) ), 1.40 (s, 3H).

LC-MS : t _R = 2.52 min (LCMS method 1), m/z = 422.1 [M + H] ⁺ .

SFC : t _R = 1.10 min (SFC method 14), ee% = 100%.

Example 12b:

¹ H NMR (CDCl ₃ 400 MHz): δ 7.39 (t, 1H), 7.18 (d, 1H), 7.10-7.08 (m, 2H), 6.52 (t, 1H), 6.36 (d, 1H), 6.24 (t) , 1H), 5.33-5.29 (m, 1H), 4.68 (s, 1H), 4.18 (dd, 1H), 2.52 (dd, 1H), 2.61-2.42 (m, 4H), 1.39 (s, 3H).

LC-MS : t _R = 2.52 min (LCMS method 1), m/z = 422.1 [M + H] ⁺ .

SFC : t _R = 1.24 min (SFC method 14), ee% = 95.8%.

Example 13a : N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide

and

Example 13b : N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide

Step 1: Preparation of N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide

prepared from IIa and IIIg .

Step 2: ( R ) -N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexane Amide and ( S ) -N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide separation of

Separation of N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide by chiral SFC did

Example 13a:

¹ H NMR (CDCl ₃ 400 MHz): δ 7.37 (t, 1H), 7.19 (d, 1H), 7.10-7.07 (m, 2H), 6.76 (d, 1H), 6.51 (t, 1H), 6.23 (t) , 1H), 5.35-5.30 (m, 1H), 4.19-4.08 (m, 2H), 3.39 (s, 1H), 2.51-2.34 (m, 2H), 1.84-1.76 (m, 1H), 1.43 (d , 2H), 1.27 (s, 3H), 0.98-0.95 (m, 6H).

LC-MS : tR = 2.54 min (LCMS Method 1), m/z = 396.1 [M + H] + .

SFC : tR = 2.40 min (SFC method 15), ee% = 99.3%.

Example 13b :

¹ H NMR (CDCl ₃ 400 MHz): δ 7.37 (t, 1H), 7.19 (d, 1H), 7.10 (s, 1H), 7.07 (d, 1H), 6.73 (d, 1H), 6.51 (t, 1H) ), 6.23 (t, 1H), 5.35-5.31 (m, 1H), 4.19-4.09 (m, 2H), 3.37 (s, 1H), 2.50-2.34 (m, 2H), 1.85-1.76 (m, 1H) ), 1.45 (d, 2H), 1.26 (s, 3H), 1.00-0.94 (m, 6H).

LC-MS : t _R = 2.54 min (LC-MS Method 1), m/z = 396.1 [M + H] ⁺ .

SFC : t _R = 2.66 min (SFC method 15), ee% = 98.8%.

Example 14a : N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide

and

Example 14b : N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide

Step 1: Preparation of N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide

prepared from IIa and IIIf .

Step 2: ( S ) -N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentane Amide and ( R ) -N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide separation of

N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide was synthesized using chiral SFC separated.

Example 14a :

¹ H NMR (CDCl ₃ 400 MHz): δ 7.34 (t, 1H), 7.16 (d, 1H), 7.07 (s, 1H), 7.04 (d, 1H), 6.76 (d, 1H), 6.48 (t, 1H), 6.20 (t, 1H), 5.32-5.27 (m, 1H), 4.16-4.12 (m, 1H), 4.09-4.04 (m, 1H), 3.39 (s, 1H), 2.49-2.28 (m, 2H), 1.77-1.70 (m, 1H), 1.15 (s, 3H), 0.93-0.89 (m, 6H).

LC-MS : t _R =2.41 min (LCMS method 1), m/z =382.0 [M + H] ⁺ .

SFC : t _R = 2.44 min (SFC method 15), ee% = 100%.

Example 14b :

¹ H NMR (CDCl ₃ 400 MHz): δ 7.35 (t, 1H), 7.16 (d, 1H), 7.08 (s, 1H), 7.04 (d, 1H), 6.79 (d, 1H), 6.48 (t, 1H), 6.19 (t, 1H), 5.31-5.26 (m, 1H), 4.14-4.10 (m, 1H), 4.08-4.04 (m, 1H), 3.43 (s, 1H), 2.48-2.28 (m, 2H), 1.75-1.69 (m, 1H), 1.12 (s, 3H), 0.92-0.88 (m, 6H).

LC-MS : t _R =2.41 min (LCMS method 1), m/z = 382.0 [M + H]+.

SFC : t _R = 2.68 min (SFC method 15), ee% = 97.4%.

Example 15a: N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropanamide

and

Example 15b: N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropanamide

Step 1: N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydr Preparation of hydroxypropanamide

prepared from IIa and IIIh .

Step 2: ( S ) -N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl) -3-hydroxypropanamide and ( R ) -N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3 -Isolation of dimethylcyclobutyl)-3-hydroxypropanamide

N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropanamide was isolated by chiral SFC.

Example 15a:

¹ H NMR (DMSO-d6 400 MHz): δ 8.41 (d, 1H), 7.40 (t, 1H), 7.26 (d, 1H), 7.21 (t, 1H), 7.20 (s, 1H), 7.09 (d , 1H), 6.67 (t, 1H), 5.17-5.12 (m, 1H), 4.61 (d, 1H), 3.98-3.97 (m, 2H), 3.70-3.67 (m, 1H), 2.16-2.11 (m) , 3H), 1.64 1.52 (m, 4H), 1.09 (s, 3H), 0.99 (s, 3H).

LC-MS : t _R =2.35 min (LC-MS method 3), m/z = 408.1 [M + H] ⁺ .

SFC : t _R = 2.32 min (SFC method 16), ee% = 99.7

Example 15b:

¹ H NMR (DMSO-d6 400 MHz): δ 8.43 (d, 1H), 7.40 (t, 1H), 7.24 (d, 1H), 7.22 (t, 1H), 7.18 (s, 1H), 7.08 (d , 1H), 6.67 (t, 1H), 5.14-5.10 (m, 1H), 4.63 (d, 1H), 3.99-3.96 (m, 2H), 3.70-3.67 (m, 1H), 2.13-2.08 (m) , 3H), 1.64-1.49 (m, 4H), 1.06 (s, 3H), 0.97 (s, 3H).

LC-MS : tR = 2.34 min (LCMS method 3), m/z = 408.1 [M + H] ⁺ .

SFC : t _R = 2.64 min (SFC method 16), ee% = 98.7%.

Example 16a: 3-cyclopentyl- N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide

and

Example 16b: 3-cyclopentyl- N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide

Step 1: Preparation of 3-cyclopentyl- N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide

prepared from IIa and IIIi .

Step 2: ( S )-3-cyclopentyl- N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide and ( R )-3-cyclopentyl- N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide.

3-cyclopentyl- N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide was isolated by chiral SFC .

Example 16a:

¹ H NMR (DMSO-d6 400 MHz) δ 8.43 (d, 1H), 7.39 (t, 1H), 7.27-7.25 (m, 1H), 7.20 (s, 1H), 7.20 (t, 1H), 7.08 ( d, 1H), 6.66 (t, 1H), 5.16-5.14 (m, 1H), 4.61 (d, 1H), 3.99-3.97 (m, 2H), 3.69-3.65 (m, 1H), 2.26-2.25 ( m, 2H), 1.80-1.76 (m, 1H), 1.64-1.22 (m, 8H).

LC-MS : t _R = 2.48 min (LC-MS method 1), m/z = 394.1 [M + H] ⁺ .

SFC : t _R = 2.64 min (SFC method 17), ee% = 98.8%.

Example 16b:

¹ H NMR (DMSO-d6 400 MHz): δ 8.41 (d, 1H), 7.36 (d, 1H), 7.20 (d, 1H), 7.18 (t, 1H), 7.15 (s, 1H), 7.04 (m , 1H), 6.63 (t, 1H), 5.13-5.07 (m, 1H), 4.59 (d, 1H), 3.98-3.91 (m, 2H), 3.66-3.62 (m, 1H), 2.23-2.19 (m) , 2H), 1.73-1.69 (m, 1H), 1.60-1.33 (m, 8H).

LC-MS : t _R = 2.27 min (LC-MS method 2), m/z = 394.2 [M + H] ⁺ .

SFC : t _R = 3.08 min (SFC method 17), ee% = 100%

Example 36a: 3-(1-fluorocyclopropyl)-3-hydroxy-N-((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl) butanamide

and

Example 36b: 3-(1-fluorocyclopropyl)-3-hydroxy-N-((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl) butanamide

Step 1: Preparation of 3-(1-fluorocyclopropyl)-3-hydroxy-N-((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide

prepared from IIp and IIIc .

Step 2: ( R )-3-(1-fluorocyclopropyl)-3-hydroxy- N -(( R )-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl) butanamide and ( S )-3-(1-fluorocyclopropyl)-3-hydroxy- N -(( R )-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl) Isolation of butanamide

3-(1-fluorocyclopropyl)-3-hydroxy-N-((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide by chiral SFC separated.

Example 36a:

¹ H NMR (CDCl ₃ 400 MHz): δ 7.38 (t, 1H), 7.29 (d, 1H), 7.22 (s, 1H), 7.16 (d, 1H), 6.58 (d, 1H), 5.18-5.13 (m) , 1H), 5.04(s, 1H), 3.70-3.62 (m, 2H), 3.38 (s, 3H), 2.72-2.68 (m, 1H), 2.54-2.50 (m, 1H), 1.36 (s, 3H) ), 0.81-0.53 (m, 4H).

LC-MS: t _R =2.43 min (LCMS Method 1), m/z = 380.0 [M + H]+.

SFC : tR = 1.29 min (SFC method 21), ee% = 99.6%.

Example 36b:

¹ H NMR (CDCl ₃ 400 MHz): δ 7.38 (t, 1H), 7.28-7.27 (m, 1H), 7.20 (s, 1H), 7.15 (d, 1H), 6.58 (d, 1H), 5.18-5.14 (m, 1H), 4.93 (s, 1H), 3.70-3.62 (m, 2H), 3.38 (s, 3H), 2.71 (dd, 1H), 2.52 (dd, 1H), 1.35 (s, 3H), 1.00-0.86 (m, 4H).

LC-MS: t _R =2.53 min (LCMS Method 1), m/z = 380.0 [M + H]+.

SFC: t _R =1.76 min (SFC method 22), ee% = 81.4%.

Example 17: ( S )- N -(( R )-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

Step 1: Preparation of ( S ) -N -(( R )-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

( R )-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethan-1-amine hydrochloride ( IIc ) (0.2 g), (3 S )-3 in DCM (10 mL) To a solution of -hydroxy-4,4-dimethyl-pentanoic acid ( IIIa ) (144 mg) and HATU (375 mg) was added DIEA (319 mg). The mixture was stirred at 20° C. for 16 h and concentrated. Purification of the crude ( S ) -N -(( R )-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide was created.

¹ H NMR (CDCl ₃ 400 MHz): δ 7.33 (t, 1H), 7.17 (d, 1H), 7.08 (s, 1H), 7.03 (d, 1H), 6.49 (m, 1H), 6.51 (t, 1H) ), 5.18-5.14 (m, 1H), 3.80-3.78 (m, 1H), 3.72-3.66 (m, 2H), 3.42 (d, 1H), 3.35-3.25 (m, 1H), 2.44-2.26 (m) , 2H), 0.93 (s, 9H), 0.57-0.45 (m, 4H).

LC-MS : t _R = 2.40 min (LCMS method 1), m/z = 372.1 [M + H] ⁺ .

SFC : t _R = 1.988 min (SFC method 7), ee% = 97.5%.

The following examples were prepared by a methodology analogous to that described for Example 17 using the relevant intermediates:

Example 18: ( S )- N -(( R )-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide

prepared from IIe and IIIa .

¹ H NMR (CDCl ₃ 400 MHz): δ 7.41-7.36 (m, 1H), 7.18 (d, 1H), 7.10-7.08 (m, 2H), 6.67 (d, 1H), 6.52 (t, 1H), 5.37-5.32 (m, 1H), 4.28-4.20 (m, 1H), 3.69 (d, 1H), 2.93 (s, 1H), 2.47-2.43 (m, 1H), 2.36-2.29 (m, 1H), 0.93 (s, 9H).

LC-MS : t _R =2.38 min (LCMS method 3), m/z = 400.0 [M+H] ⁺ .

SFC : t _R = 2.11 min (SFC method 4), ee% = 96.4%.

Example 19: ( S )- N -(( R )-1-(3-(trifluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide

¹ H NMR (CDCl ₃ 400 MHz): δ 7.35 (t, 1H), 7.21-7.19 (m, 1H), 7.13-7.11 (m, 2H), 6.65 (d, 1H), 5.32-5.27 (m, 1H) ), 4.21-4.13 (m, 1H), 3.64-3.61 (m, 1H), 2.83 (d, 1H), 2.41-2.36 (m, 1H), 2.29-2.25 (m, 1H), 0.86 (s, 9H) ).

LC-MS : t _R = 2.56 min (LCMS method 3), m/z = 418.0 [M+H] ⁺ .

HPLC : t _R = 13.54 min (HPLC method 2), ee% = 65.9%

Example 20: ( S )- N -(( S )-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxy-4,4-dimethylpentanamide

prepared from IIg and IIIa .

¹ H NMR (CDCl ₃ 400 MHz): δ 7.33 (t, 1H), 7.14 (d, 1H), 7.03-7.00 (m, 2H), 6.52 (t, 1H), 6.22-6.20 (m, 1H), 4.97 (q, 1H), 3.68-3.64 (m, 1H), 3.31 (d, 1H), 2.39-2.24 (m, 2H), 1.75-1.72 (m, 2H), 1.36-1.29 (m, 2H), 0.95-0.91 (m, 12H).

LC-MS : t _R = 2.30 min (LCMS method 3), m/z =344.1 [M + H] ⁺ .

SFC : t _R = 2.13 min (SFC method 1), ee% = 98.7%.

Example 21: ( S )- N -(( S )-1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutyl)-3-hydroxy-4,4-dimethylpentanamide

IIh and IIIa .

¹ H NMR (CDCl ₃ 400 MHz): δ 7.36 (t, 1H), 7.14 (d, 1H), 7.05 (m, 2H), 6.52 (t, 1H), 6.25 (d, 1H), 5.84 (tt, 1H) ), 5.03 (q, 1H), 3.68 (m, 1H), 2.97 (d, 1H), 2.40-2.21 (2H), 1.98-1.77 (4H), 0.91 (s, 9H).

LC-MS : t _R =2.43 min (LCMS method 1), m/z = 380.0 [M + H] ⁺ .

HPLC : t _R = 14.01 min (HPLC method 3), ee% = 95.7%.

Example 22: ( S )- N -(( S )-1-(3-(difluoromethoxy)phenyl)-3,3-difluoropropyl)-3-hydroxy-4,4-dimethylpentanamide

prepared from IIi and IIIa .

¹ H NMR (CDCl ₃ 400 MHz): δ 7.35 (t, 1H), 7.14 (d, 1H), 7.05-7.03 (m, 2H), 6.50 (t, 1H), 6.53-6.50 (m, 1H), 5.80 (tt, 1H), 5.30-5.24 (m, 1H), 3.66 (dd, 1H), 2.89 (s, 1H), 2.40-2.22 (m, 4H), 0.89 (s, 9H).

LC-MS : t _R =2.63 min (LCMS method 1), m/z = 366.2 [M + H] ⁺ .

HPLC : t _R = 13.43 min (HPLC method 1), ee% = 96.7%.

Example 23: ( S )- N -(( S )-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

IIj and IIIa .

¹ H NMR (CDCl ₃ 400 MHz): δ 7.34-7.30 (m, 1H), 7.16-7.12 (m, 1H), 7.04-6.97(m, 2 H), 6.31 (t, 1 H), 6.14 (brs) , 1 H), 5.12-5.06 (m, 1 H), 3.67-3.62 (m, 1 H), 3.29 (s, 1 H), 2.37-2.31 (m, 1 H), 2.26-2.19 (m, 1 H), 1.47-1.43 (m, 3 H), 0.98 (s, 9 H).

LC-MS : t _R = 2.155 min (LCMS method 2), m/z = 316.1 [M + H] ⁺ .

SFC : t _R = 2.416 min (SFC method 8), ee% = 100%.

Example 24: ( S )- N -(( S )-2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

prepared from IIm and IIIa .

¹ H NMR (400 MHz, DMSO-d6): δ 8.66 (d, 1H), 7.51 (t, 1H), 7.45-7.43 (m, 2H), 7.30 (d, 1H), 5.25-5.23 (m, 1H) ), 4.62 (d, 1H), 3.57-3.51 (m, 1H), 3.00 (dd, 2H), 2.31-2.11 (m, 2H), 0.81 (s, 9H).

LC-MS : t _R =2.42 min (LSMS method 1), m/z = 359.2 [M + H] ⁺ .

HPLC : t _R = 12.56 min (HPLC method 4), ee% = 100%.

Example 25: ( S )- N -(( S )-3-cyano-1-(3-(trifluoromethoxy)phenyl)propyl)-3-hydroxy-4,4-dimethylpentanamide

prepared from IIn and IIIa .

¹ H NMR (CDCl ₃ 400 MHz): δ 7.42 (t, 1H), 7.24 (m, 1H), 7.18 (d, 1H), 7.13 (s, 1H), 6.49 (d, 1H), 5.19-5.13 (m) , 1H), 3.75-3.71 (m, 1H), 2.82 (d, 1H), 2.45-2.40 (m, 3H), 2.30-2.27 (m, 1H), 2.23-2.16 (m, 2H), 0.92 (s) , 9H).

LC-MS : t _R =2.44 min (LCMS method 1), m/z = 373.2 [M + H] ⁺ .

SFC : t _R = 1.47 min (SFC method 9), ee% = 95.8%.

Example 26: ( R )-2-(3,3-difluoro-1-hydroxycyclobutyl)- N -(2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)acetamide

prepared from IIa and IIIb .

¹ H NMR (CDCl ₃ 400 MHz): δ 7.37 (t, 1H), 7.15 (d, 1H), 7.09-7.06 (m, 2H), 6.50 (t, 1H), 6.32 (t, 1H), 6.23 ( m, 1H), 5.29-5.24 (m, 1H), 4.74 (s, 1H), 4.17 (dd, 1H), 4.08 (dd, 1H), 2.75-2.72 (m, 2H), 2.68 (s, 2H) , 2.62-2.56 (m, 2H).

LC-MS : t _R =2.39 min (LCMS method 1), m/z = 402.1 [M + H] ⁺ .

SFC : t _R = 1.87 min (SFC method 1), ee% = 100%

Example 27: ( R )-2-(3,3-difluoro-1-hydroxycyclobutyl)- N -(2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide

prepared from IIb and IIIb .

¹ H NMR (CDCl ₃ 400 MHz): δ 7.35 (t, 1H), 7.14-7.09 (m, 3H), 6.18 (t, 1H), 6.21 (d, 1H), 5.23 (m, 1H), 4.66 (br s, 1H), 4.13 (dd, 1H), 4.04 (dd, 1H), 2.72-2.66 (m, 2H), 2.64 (s, 2H), 2.56-2.50 (m, 2H).

LC-MS : t _R = 2.53 min (LC-MS method 1), m/z = 420.2 [M+H] ⁺ .

HPLC : t _R = 12.77 min (HPLC method 2), ee% = 86.7%.

Example 28: ( R )- N -(2-cyclopropoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide

prepared from IId and IIIb .

¹ H NMR (CDCl ₃ 400 MHz): δ 7.37 (t, 1H), 7.22 (d, 1H), 7.15 (m, 2H), 6.40 (d, 1H), 5.13 (m, 1H), 4.92 (s, 1H) ), 3.81 (m, 1H), 3.69 (m, 1H), 3.29 (m, 1H), 2.78-2.52 (6H), 0.57-0.44 (4H).

LC-MS : t _R = 2.53 min (LC-MS method 1), m/z = 410.0 [M + H] ⁺ .

SFC : t _R = 1.50 min (SFC method 7), ee% = 99.7%

Example 29: ( R )- N -(2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide

prepared from IIe and IIIb .

¹ H NMR (CDCl ₃ 400 MHz): δ 7.35 (d, 1H), 7.15 (d, 1H), 7.06 (s, 1H), 7.05 (d, 1H), 6.51 (t, 1H), 6.39 (d, 1H), 5.15-5.10 (m, 1H), 4.98 (m, 1H), 3.83-3.67 (m, 2H), 3.31-3.30 (m, 1H), 2.79-2.75 (m, 2H), 2.68 (d, 2H), 2.64-2.52 (m, 2H), 0.60-0.46 (m, 4H).

LC-MS : t _R = 2.40 min (LC-MS method 1), m/z = 392.1 [M + H] ⁺ .

SFC : t _R = 2.32 min (SFC method 6), ee% = 100.00%

Example 30: ( R )-2-(3,3-difluoro-1-hydroxycyclobutyl)- N -(1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)acetamide

prepared from IIe and IIIb .

¹ H NMR (CDCl ₃ 400 MHz): δ 7.39 (t, 1H), 7.15 (d, 1H), 7.08 (m, 2H), 6.51 (t, 1H), 6.30 (m, 1H), 5.32 (m, 1H) ), 4.63 (s, 1H), 4.23 (m, 2H), 2.76-2.57 (6H).

LC-MS : t _R = 2.48 min (LC-MS method 1), m/z = 420.0 [M + H] ⁺ .

SFC : t _R = 12.96 min (HPLC method 2), ee% = 75.5%

Example 31: ( S )-2-(3,3-difluoro-1-hydroxycyclobutyl)- N -(1-(3-(difluoromethoxy)phenyl)butyl)acetamide

prepared from IIg and IIIb .

¹ H NMR (CDCl ₃ 400 MHz): δ 7.35 (t, 1H), 7.13 (d, 1H), 7.04 (m, 2H), 6.52 (t, 1H), 5.91 (m, 1H), 5.04 (s, 1H), 4.96 (q, 1H), 2.78-2.56 (6H), 1.76 (m, 2H), 1.34 (m, 2H), 0.95 (t, 3H).

LC-MS : t _R =2.44 min (LC-MS method 1), m/z =364.0 [M + H] ⁺ .

SFC : t _R = 1.71 min (SFC method 10), ee% = 94.8%.

Example 32: ( S )-2-(3,3-difluoro-1-hydroxycyclobutyl)- N -(1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutyl)acetamide

IIh and IIIb .

¹ H NMR (CDCl ₃ 400 MHz): δ 7.38 (t, 1H), 7.13 (d, 1H), 7.08 (d, 1H), 7.04 (s, 1H), 6.52 (t, 1H), 5.90 (d, 1H) ), 5.85 (tt, 1H), 5.00 (q, 1H), 4.82 (s, 1H), 2.78-2.54 (6H), 2.00 (m, 2H), 1.86 (m, 2H).

LC-MS : t _R = 2.50 min (LCMS method 1), m/z = 400.1 [M + H] ⁺ .

HPLC : t _R =12.48 min (HPLC method 2), ee% = 98.3%.

Example 33: ( S )-2-(3,3-difluoro-1-hydroxycyclobutyl)- N -(1-(3-(trifluoromethoxy)phenyl)propyl)acetamide

prepared from IIl and IIIb .

¹ H NMR (CDCl ₃ 400 MHz): δ 7.38 (t, 1H), 7.20 (d, 1H), 7.14 (d, 1H), 7.10 (s, 1H), 5.89 (d, 1H), 4.99 (brs, 1H) ), 4.89 (q, 1H), 2.77-2.70 (m, 2H), 2.63 (d, 2H), 2.60-2.50 (m,2H), 1.87-1.80 (m, 2H), 0.92 (t, 3H).

LC-MS : t _R = 2.57 min (LCMS method 1), m/z = 368.1 [M + H] ⁺ .

SFC : t _R = 13.09 min (SFC method 1), ee% = 100%

Example 34: ( S )- N -(2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide

prepared from IIm and IIIb .

¹ H NMR (CDCl ₃ 400 MHz): δ 7.46 (t, 1H), 7.30 (d, 1H), 7.24 (m, 1H), 7.19 (s, 1H), 6.51 (s, 1H), 5.34-5.29 (m , 1H), 4.44 (s, 1H), 3.09-3.03 (m, 1H), 2.91-2.89 (m, 1H), 2.77-2.73 (m, 2H), 2.70-2.53 (m, 4H).

LC-MS : t _R =2.257 min (LC-MS Method 1), m/z = 379.0 [M+H] ⁺ .

SFC : t _R = 2.60 min (SFC method 11), ee% = 100%.

Example 35: ( S )- N -(3,3-difluoro-1-(3-(trifluoromethoxy)phenyl)propyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide

prepared from IIo and IIIb .

¹ H NMR (CDCl ₃ 400 MHz): δ 7.44 (t, 1H), 7.23 (m, 2H), 7.15 (s, 1H), 6.15 (br d, 1H), 5.83 (tt, 1H), 5.32 (m , 1H), 4.69 (s, 1H), 2.73 (m, 2H), 2.66 (s, 2H), 2.62-2.34 (4H).

LC-MS : t _R = 2.53 min (LC-MS method 1), m/z = 404.1 [M + H] ⁺ .

SFC : t _R = 1.66 min (SFC method 19), ee% = 98.5%

Claims (24)

A compound of formula (I) or a pharmaceutically acceptable salt of any of these compounds:
[Formula I]

(In the above formula,
R1 is selected from the group consisting of C ₁ -C ₆ alkyl, CF ₃ , CH ₂ CF ₃ , CF ₂ CHF ₂ , C ₃ -C ₈ cycloalkyl, wherein C ₃ -C ₈ cycloalkyl is C ₁ -C ₃ may be substituted with 1 or 2 substituents selected from the group consisting of alkyl, F, CHF ₂ and CF ₃ ,
R2 is H, C ₁ -C ₆ alkyl or CF ₃ ;
R 1 and R 2 taken together form C ₃ -C ₅ cycloalkyl optionally substituted with one or two F, CHF ₂ or CF ₃ ;
R3 is C ₁ -C ₃ alkyl or CH ₂ OC _1-3 alkyl, said C ₁ -C ₃ alkyl or CH ₂ OC _{1 -} C ₃ is C≡N, three F or C ₃ -C ₅ cycloalkyl substituted alkyl;
R4 is selected from the group consisting of OCF ₃ or OCHF ₂ ). The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R4 is OCF ₃ or OCHF ₂ . The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R3 is selected from the group consisting of CH ₂ -O-CF ₃ , CH ₂ -O-cyclopropyl, CH ₂ -C≡N. 4. The compound of any one of claims 1 to 3, wherein R 1 is C ₃ -C ₄ cycloalkyl optionally substituted with 1 or 2 C ₁ -C ₃ alkyl, F, CHF ₂ or CF ₃ . or a pharmaceutically acceptable salt thereof. 5. The compound or pharmaceutical thereof according to any one of claims 1 to 4, wherein R1 and R2 are taken together to form cyclobutyl optionally substituted with one or two F, and R4 is OCF ₃ or OCHF ₂ as acceptable salts. The method of claim 1, wherein the compound is
(S)-N-((R)-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide;
(S)-N-((R)-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide;
(S)-N-((R)-1-(3-(trifluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide;
(S)-N-((S)-2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide;
(S)-N-((S)-3-cyano-1-(3-(trifluoromethoxy)phenyl)propyl)-3-hydroxy-4,4-dimethylpentanamide;
(R)-N-(2-cyclopropoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide ;
(R)-N-(2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide ;
(R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl) acetamide; or
(S)-N-(2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide or A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of pharmaceutically acceptable salts of any of these compounds. (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide;
(S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide;
(S)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide;
(R)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide;
(R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoro -methyl)cyclopropyl)propanamide;
(S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoro -methyl)cyclopropyl)propanamide;
(R)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoro methyl)cyclopropyl)propanamide;
(S)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoro methyl)cyclopropyl)propanamide;
(R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)- 3-hydroxypropanamide;
(S)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)- 3-hydroxypropanamide;
(R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)- 3-hydroxypropanamide;
(S)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)- 3-hydroxypropanamide;
(S)-3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide;
(R)-3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide;
(S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxy propanamide;
(R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxy propanamide;
(S)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxy-4,4-dimethylpentanamide;
(S)-N-((S)-1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutyl)-3-hydroxy-4,4-dimethylpentanamide;
(S)-N-((S)-1-(3-(difluoromethoxy)phenyl)-3,3-difluoropropyl)-3-hydroxy-4,4-dimethylpentanamide;
(S)-N-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide;
(R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl) acetamide;
(R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl) acetamide;
(S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(difluoromethoxy)phenyl)butyl)acetamide;
(S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutyl)ah cetamide;
(S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(trifluoromethoxy)phenyl)propyl)acetamide;
(S)-N-(3,3-difluoro-1-(3-(trifluoromethoxy)phenyl)propyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)ah cetamide;
(S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide;
(R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydro oxybutanamide;
(S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydr oxybutanamide;
(S)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydr oxybutanamide;
(R)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydr oxybutanamide;
(R)-3-cyclopropyl-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide;
(S)-3-cyclopropyl-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide;
(R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy -3-methylpentanamide;
(S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy -3-methylpentanamide;
(R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide;
(S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide;
(S)—N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide;
(R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide;
(S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3- hydroxypropanamide;
(R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3- hydroxypropanamide;
( S )-3-cyclopentyl- N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide;
( R )-3-cyclopentyl- N -(( R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide;
( R )-3-(1-fluorocyclopropyl)-3-hydroxy- N -(( R )-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide;
and ( S )-3-(1-fluorocyclopropyl)-3-hydroxy- N -(( R )-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide
or a pharmaceutically acceptable salt of any of these compounds. A pharmaceutical composition comprising the compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In need of treatment suffering from epilepsy, bipolar disorder, migraine or schizophrenia comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof. how to treat patients who A therapeutically effective amount of a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, comprising administering to the subject psychosis, mania, stress related disorder, acute stress response, bipolar depression, Major Depressive Disorder, Anxiety, Panic Attack, Social Phobia, Sleep Disorder, ADHD, PTSD, OCD, Impulsive Disorder, Personality Disorder, Schizotypal Disorder, Aggression, Chronic Pain, Neuropathy, Autism Spectrum Disorder, Huntington's Chorea, Sclerosis, Multiple A method of treating a patient in need of treatment suffering from sclerosis, Alzheimer's disease. Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof in treatment. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for the treatment of epilepsy, bipolar disorder, migraine or schizophrenia. Psychosis, Mania, Stress-Related Disorder, Acute Stress Response, Bipolar Depression, Major Depressive Disorder, Anxiety, Panic Attack, Social Phobia, Sleep Disorder, ADHD, PTSD, OCD, Impulsive Disorder, Personality Disorder, Schizotypal Disorder, Aggression, Chronic Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for the treatment of pain, neuropathy, autism spectrum disorder, Huntington's chorea, sclerosis, multiple sclerosis, Alzheimer's disease. 8. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, for the manufacture of a medicament for the treatment of epilepsy, bipolar disorder, migraine or schizophrenia. 8. The method of any one of claims 1 to 7, wherein the drug is selected from the group consisting of psychosis, mania, stress related disorder, acute stress response, bipolar depression, major depressive disorder, anxiety, panic attack, social phobia, sleep disorder, ADHD, PTSD, OCD, For the manufacture of a medicament for treating impulsive disorder, personality disorder, schizotypal disorder, aggression, chronic pain, neuropathy, autism spectrum disorder, Huntington's chorea, sclerosis, multiple sclerosis, Alzheimer's disease, a compound or a pharmaceutically acceptable thereof possible salts. 18. A compound according to any one of claims 1 to 7, or a pharmaceutical salt thereof, or a pharmaceutical salt thereof according to claim 16, for use in the treatment of epilepsy, epileptic syndrome, epileptic symptoms, treatment-resistant or refractory epilepsy, or seizures. pharmaceutical composition. Focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, generalized idiopathic epilepsy, grand seizures, superposition epilepticus, neonatal seizures, KCNQ epileptic encephalopathy (KCNQ2EE) and benign familial neonatal seizures. and other epileptic syndromes (eg, severe myoclonic epilepsy in infants, epilepsy with continuous spikes during slow wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome) ) and premature myoclonic encephalopathy Ohtahara syndrome), or stress-related seizures, hormonal changes, drugs, alcohol, infection, traumatic brain injury, stroke, brain cancer, autism spectrum disorders or metabolic disorders (such as hyponatremia) ), a compound according to any one of claims 1 to 7, or a pharmaceutical salt thereof, or a pharmaceutical composition according to claim 16. 8. A compound according to any one of claims 1 to 7, or a pharmaceutical thereof, for use in the treatment of neurodegenerative disorders such as Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, epileptic conditions as part of frontotemporal degeneration. A salt or a pharmaceutical composition according to claim 16 . A therapeutically effective amount of the compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, comprising administering to the subject epilepsy, epileptic syndrome, epilepsy symptoms, treatment-resistant or refractory epilepsy or a method of treating a patient in need of treatment suffering from a seizure. Local (partial) epilepsy with simple partial seizures, complex partial seizures comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof focal (partial) epilepsy with , epilepsy with continuous spikes during slow wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravette syndrome and premature myoclonic encephalopathy (Otahara syndrome), or stress-related seizures, hormonal changes, drugs, alcohol, infection, traumatic brain injury , stroke, brain cancer, autism spectrum disorder or metabolic disorder (e.g. hyponatremia) or for treating a patient in need thereof, or for treating a neurodegenerative disorder such as Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, frontotemporal degeneration A method for use in the treatment of an epileptic condition as part of Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for the treatment of epilepsy, epileptic syndrome, epileptic symptoms, treatment-resistant or refractory epilepsy, or seizures. focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, generalized idiopathic epilepsy, grand seizures, superposition epilepticus, neonatal seizures, KCNQ epileptic encephalopathy (KCNQ2EE) and benign familial neonatal seizures and other epileptic syndromes (e.g., severe myoclonic epilepsy in infants, epilepsy with continuous spikes during slow wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravette syndrome and premature myoclonic encephalopathy Otahara syndrome), or stress and For use in the treatment of related seizures, hormonal changes, drugs, alcohol, infections or metabolic disorders (eg hyponatremia) or as part of a neurodegenerative disorder such as Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, frontotemporal degeneration Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for the treatment of an epileptic condition. 8. A compound or a pharmaceutically acceptable compound or pharmaceutically acceptable thereof according to any one of claims 1 to 7, for the manufacture of a medicament for treating epilepsy, epileptic syndrome, epileptic symptoms, treatment-resistant or refractory epilepsy, or seizures. salt. 8. The seizure according to any one of claims 1 to 7, wherein focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, generalized idiopathic epilepsy, grand seizures, superlative epilepsy, neonatal seizures , KCNQ epileptic encephalopathy (KCNQ2EE) and benign familial neonatal convulsions and other epileptic syndromes (e.g., severe myoclonic epilepsy in infants, epilepsy with continuous spikes during slow wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravett) Syndrome and early myoclonic encephalopathy Otahara syndrome) or for use in the treatment of epileptic conditions as part of neurodegenerative disorders such as Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, frontotemporal degeneration, A compound or a pharmaceutically acceptable salt thereof.